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Thursday, October 30, 2003
6:00 am - 9:00 pm Registration Open
Friday, October 31, 2003
6:00 am - 6:00 pm Registration Open – Meeting Room Foyer (Conference Level)
6:00 am - 7:45 am Continental Breakfast – Crystal Ballroom Foyer
7:45 am - 8:00 am President’s Welcome: Michael B. Atkins, MD – Crystal Ballroom
8:00 am - 8:30 am Welcome Address: Kathryn Zoon, PhD – Crystal Ballroom
8:30 am - 9:15 am Keynote Address: Peter Parham, PhD – Crystal Ballroom
9:15 am - 12:00 pm Joint Session: Natural Killer Cells and Innate Immunity – Crystal Ballroom
10:00 am - 5:00 pm Exhibits Open – Cabinet/Judiciary Rooms
12:00 pm - 1:30 pm Poster Session Posters 1-64 (box lunches available/exhibits open) – Conference Level
1:30 pm - 4:00 pm Plenary Session: Dendritic Cells and Vaccines – Crystal Ballroom
4:15 pm - 6:00 pm Concurrent Sessions I, II & III Concurrent Session I: Adoptive Immunotherapy – Haverford/Bacarrat Ballroom Concurrent Session II: Pediatric Oncology – Old Georgetown Ballroom Concurrent Session III: Imaging – Waterford/Lalique Ballroom
6:00 pm - 6:30 pm iSBTc Membership/Business Meeting (iSBTc Members Only) – Old Georgetown Ballroom
6:30 pm - 7:30 pm Member/Sponsor Reception (Invitation Only) – Crystal Ballroom Foyer
Saturday, November 1, 2003
7:00 am - 6:00 pm Registration Open – Meeting Room Foyer (Conference Level)
7:00 am - 7:45 am Continental Breakfast – Crystal Ballroom Foyer
8:00 am - 8:45 am Keynote Address: Alberto Mantovani, MD – Crystal Ballroom
10:00 am - 4:00 pm Exhibits Open – Cabinet/Judiciary Rooms – Crystal Ballroom
8:45 am - 11:30 am Joint Session: Inhibiting of Inflammatory Mediators – Crystal Ballroom
11:30 am - 1:00 pm Poster Sessions 65-122 (box lunches available/exhibits open) – Conference Level
1:00 pm - 2:20 pm Presidential Session sponsored by Aventis – Crystal Ballroom
3:00 pm - 4:45 pm Concurrent Sessions I, II & III Concurrent Session I: Cytokines-Polymorphisms – Waterford/Lalique Ballroom Concurrent Session II: 2002 Angiogenesis Monitoring Workshop Follow-Up – Haverford/Lalique Ballroom Concurrent Session III: Genomics – Old Georgetown Ballroom
5:00 pm - 6:30 pm Presidential Reception (Announcement of Presidential Award Winner) – Crystal Ballroom Foyer
Sunday, November 2, 2003
7:30 am - 12:00 pm Registration Open – Meeting Room Foyer (Conference Level)
7:30 am - 8:00 am Continental Breakfast – Crystal Ballroom Foyer
8:00 am - 10:30 am Joint Session: New Agents in Development – Crystal Ballroom Foyer
Program at a Glance
Session sponsored by
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Welcome from the President
Michael B. Atkins, MD
Dear Colleagues,
Welcome to the 18th Annual Meeting of The International Society for Biological Therapy of Cancer (iSBTc) and Bethesda, MD.
The iSBTc has been on the cutting edge of cancer research since its inception as the Society for Biological Therapy in 1984. Now, as biologic therapy of cancer comes of age, the iSBTc continues to grow in its role as the organization where immunologic and biologic approaches to cancer treatment are presented, discussed and critically evaluated.
The year 2003 has brought about an increased global focus and an expanded and more vital mission for the Society. To this end, we have expanded our programming to include the many exciting programs detailed in the following pages.
Programs such as the Primer on Tumor Immunology and Biological Therapy of Cancer, the Workshop on Cancer Biometrics, and the Consensus Conference on Patient Specific Biologic Therapy now surround the 18 th Annual Meeting and will serve to further iSBTc’s position as the forum where basic and clinical investigators from academic, regulatory, and biopharmaceutical venues discuss their common interests. We hope you have chosen to
attend some of these programs and find them worthwhile.
In addition to your participation in the Annual Meeting, Workshops and Consensus Conferences, we hope that you will join this excitement by becoming an active member of iSBTc. We have much to do and welcome active and enthusiastic participation from our membership.
Don’t forget to mark your calendar for the 19 th Annual Meeting of iSBTc to be held November 4-7, 2004 at the Fairmont Hotel in San Francisco, CA.
Sincerely,
Michael B. Atkins, MD President International Society for Biological Therapy of Cancer
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Table of Contents
611 East Wells Street Milwaukee, WI 53202 414-271-2456 Fax: 414-276-3349 Email: info@isbtc.org
www.isbtc.org
iSBTc Leadership . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Sponsors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
General Meeting Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Hotel Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Program Schedule
18th Annual Meeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Annual Meeting Faculty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Oral Abstract Presenters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
iSBTc Membership Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
iSBTc Membership Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
iSBTc Exhibitor Listing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
iSBTc Exhibit Floor Plan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Oral Abstracts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Poster Sessions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
18th Annual Meeting October 30 - November 2, 2003
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Board of Directors
Officers President Michael B. Atkins, MD Beth Israel Deaconess Medical Center Boston, MA
Vice President Ulrich Keilholz, MD UKBF, Free University Berlin, Germany
Treasurer Elizabeth A. Repasky, PhD Roswell Park Cancer Institute Buffalo, NY
Immediate Past President Robert O. Dillman, MD Hoag Cancer Center Newport Beach, CA
Board Members Janice P. Dutcher, MD Our Lady of Mercy Medical Center Comprehensive Cancer Center Bronx, NY
Bernard A. Fox, PhD Earl A. Chiles Research Institute Portland, OR
Peter Hersey, MD, PhD Newcastle Mater Hospital Newcastle, Australia
Kim Margolin, MD City of Hope Duarte, CA
James J. Mulé, PhD H. Lee Moffitt Cancer Center and Research Institute Tampa, FL
James L. Murray, MD MD Anderson Cancer Center Houston, TX
Craig L. Slingluff, Jr., MD University of Virginia Charlottesville, VA
Mario Sznol, MD Vion Pharmaceuticals New Haven, CT
Jon M. Wigginton, MD National Cancer Institute Frederick, MD
Staff Tara Withington Executive Director
Laura M. Kalies Meeting & Membership Manager
Chloe Tolzmann Program Coordinator
Cheryl Kutchera Administrative Assistant
Kay A. Whalen Managing Partner
Scientific Program Committee Neil Berinstein, MD Aventis Pasteur Toronto, Canada
Janice P. Dutcher, MD Our Lady of Mercy Medical Center Comprehensive Cancer Center Bronx, NY
Francesco Marincola, MD National Institutes of Health Bethesda, MD
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Benefactors:
National Cancer InstituteCenter for Cancer Research
Co-Sponsors:
Supporters:
Contributors:
Patrons:
18th Annual Meeting Sponsors
Annual Meeting Break:
Session Sponsors:
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Other Sponsors
Cancer Biometrics Workshop Sponsors: Consensus Conference on
Patient Specific Therapy Sponsors:
Primer on Tumor Immunology and Biological Therapy of Cancer Sponsors:
BD Biosciences
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General Meeting Information
iSBTc Presidential Award Receipients 1991 – Pittsburgh, PA Judith Kantor, PhD National Cancer Institute – Bethesda, MD 1992 – Williamsburg, VA Carol A. Nieroda, MD National Cancer Institute – Bethesda, MD 1993 – Nashville, TN David G. Maloney, MD, PhD Stanford University – Stanford, CA 1994 – Napa, CA Laurence Zitvogel, MD, PhD University of Pittsburgh – Pittsburgh, PA 1995 – Williamsburg, VA Jon M. Wigginton, MD National Cancer Institute – Frederick, MD 1996 – Washington, DC Carmen Scheibenbogen, MD University Hospital Benjamin Franklin Free University, Berlin – Berlin, Germany 1997 – Pasadena, CA Pia M. Challita-Eid, PhD University of Rochester Cancer Center – Rochester, NY Tadashi Osaki, MD, PhD University of Pittsburgh – Pittsburgh, PA 1998 – Pittsburgh, PA Clemens Esche, MD University of Pittsburgh – Pittsburgh, PA 1999 – Boston, MA Roopa Srinivasan, PhD Memorial Sloan Kettering Cancer Center – New York, NY 2000 – Seattle, WA Robbie Malliard University of Pittsburgh – Pittsburgh, PA 2000 – Berlin, Germany Annette Paschen, MD University Clinics of Mannheim – Mannheim, Germany 2001 – Bethesda, MD Julia A. Coronella, PhD University of Arizona Arizona Cancer Center – Tucson, AZ 2002 – San Diego, CA Erin B. Dickerson, PhD Univ. of Wisconsin-Madison School of Veterinary Medicine – Madison, WI 2003 – Find out at the Presidential Reception Saturday at 5:30 – Crystal Ballrrom Foyer
The 18th Annual Meeting of the International Society for Biological Therapy of Cancer (iSBTc) will be held October 30 through November 2, 2003 at the Hyatt Regency, Bethesda, Maryland.
Meeting features include Keynote Addresses by Peter Parham, PhD from Stanford University School of Medicine and Alberto Mantovani, MD from the Mario Negri Institute of Pharmacological Research – Italy.
The Society’s distinguished faculty will lead sessions featuring Natural Killer Cells & Innate Immunity, Dendritic Cells & Other Vaccines, Adoptive Immunotherapy, Pediatric Oncology, Imaging, Inhibiting of Inflammatory Mediators, Cytokines-Polymorphisms, Genomics, New Agents in Development, as well as a follow-up to the 2002 Angiogenesis Monitoring Workshop. Other aspects of this important and exciting meeting include a Primer on Tumor Immunology and Biological Therapy of Cancer, (cochaired by Dr. Robert O. Dillman and Dr. Elizabeth Repasky) a workshop on Cancer Biometrics: Identifying Biomarkers & Surrogates of Tumor in Patients, (co-chaired by Dr. Nabil Hanna, Dr. Michael Lotze and Dr. Ena Wang) on Thursday, October 30, 2003 and a Consensus Conference on Patient Specific Therapy (co-chaired by Dr. Robert Oldham, Dr. Kenneth Foon and Dr. Larry Kwak) on Sunday, November 2, 2003.
In addition to the scheduled scientific sessions, this year’s meeting will include a members/sponsors-only reception on Friday evening and a Saturday evening Presidential Reception (where the winner of the iSBTc Presidential Award will be announced), as well as daily exhibit and poster sessions. These activities will provide meeting attendees with the opportunity to network with colleagues in cancer research.
Registration Desk Registration packets will be ready for pick up at the Registration Desk for those who registered prior to the meeting. Registration for all programs will also be accepted on-site. Separate registration fees are required for the Primer, Workshop and Consensus Conference.
Registration Desk Hours Thursday, October 30 6:00 am - 9:00 pm
Friday, October 31 6:00 am - 6:00 pm
Saturday, November 1 7:00 am - 6:00 pm
Sunday, November 2 7:30 am - 12:00 pm
Exhibit Hall Hours Friday, October 31 10:00 am - 5:00 pm
Saturday, November 1 10:00 am - 4:00 pm
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General Meeting/Hotel Information
Washington D.C./Bethesda Information Attire for the iSBTc Annual Meeting is Business Casual. Bethesda weather in October/November ranges from a high of 57°F/14°C to a low of 29°F/4°C.
For information on things to do in Bethesda and Washington D.C., contact the Washington, D.C. Convention and Tourism Corporation 1212 New York Avenue, NW, Suite 600, Washington, D.C. 20005 Ph: 202/789-7000 Fax: 202/789-7037
or www.washington.org.
Hotel Information Hyatt Regency Bethesda One Bethesda Metro Center Bethesda, MD 20814 USA Ph: 301/657-1234 Fax: 301/657-6453
POSTERS
POSTERS
EXHIBIT HALL
REGISTRATION
Hyatt Regency Bethesda
Program printing sponsored by
SCIENTIFIC SESSIONS
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Thursday, October 30, 2003
6:00 am - 9:00 pm Registration Open – Meeting Room Foyer (Conference Level)
Friday, October 31, 2003
6:00 am - 6:00 pm Registration Open – Meeting Room Foyer (Conference Level) 6:00 am - 7:45 am Continental Breakfast in Crystal Ballroom Foyer 7:45 am - 8:00 am President’s Welcome – Crystal Ballroom
Michael B. Atkins, MD Beth Israel Deaconess Medical Center
8:00 am - 8:30 am Welcome Remarks - FDA Update – Crystal Ballroom Kathryn C. Zoon, PhD Food and Drug Administration, Center for
Biologics Evaluation and Research
KEYNOTE ADDRESS – Crystal Ballroom 8:30 am - 9:15 am Immunogenetics, Diversity and Clinical Relevance of Killer Cell Immunoglobulin-like Receptors
Peter Parham, PhD Stanford University School of Medicine
JOINT SESSION – Crystal Ballroom 9:15 am - 12:00 pm Natural Killer Cells & Innate Immunity Co-Chairs: Eric O. Long, PhD
National Institute of Allergy and Infectious Diseases-National Institutes of Health John R. Ortaldo, PhD National Cancer Institute — Frederick Cancer R&D Center
9:15 am - 9:45 am Significance of the Human NKG2D Receptor and its Tumor-Associated Ligands Veronika Groh-Spies, MD
Fred Hutchinson Cancer Research Center
9:45 am - 10:15 am CD1d-Restricted ‘NKT’ Cells and Myeloid Dendritic Cell IL-12 Production Jenny Gumperz, PhD
Brigham & Women’s Hospital
10:00 am - 5:00 pm EXHIBITS OPEN Cabinet/Judiciary Rooms
10:15 am - 10:45 am Refreshment Break 10:45 am - 11:15 am Hydrodynamic IL-2 cDNA Injection: Modulation of NK Inate Function John R. Ortaldo, PhD
National Cancer Institute — Frederick Cancer R&D Center
11:15 am - 11:30 am NK Cells Provide Dendritic CellMediated Help for Th1 and CTL Responses: Two Signal Requirement for the Induction of NK Cell Helper Function Robbie B. Mailliard
University of Pittsburgh Cancer Center
11:30 am - 11:45 am Critical Role of the Family Ligands in NK Cell-Dendritic Cell Interaction Nikola L. Vujanovic, MD, PhD University of Pittsburgh
11:45 am - 12:00 pm T Cell Independent Control of Murine Neuroblastoma by CD40 Monoclonal Antibody Therapy Hillary Lum
University of Wisconsin Medical School
12:00 pm - 1:30 pm Poster Session Posters 1-64 (authors must be present) Box lunches will be available in Cabinet/ Judiciary rooms
PLENARY SESSION – Crystal Ballroom 1:30 pm - 4:00 pm Dendritic Cells & Vaccines Co-Chairs: Jacques Banchereau, PhD
Baylor Institute for Immunology Research Neil Berinstein, MD Aventis Pasteur
1:30 pm - 1:55 pm DC-T Cell Cross Talk Determines the Balance between Immune Tolerance and Activation Drew Pardoll, MD, PhD
Johns Hopkins University School of Medicine
1:55 pm - 2:20 pm Dendritic Cells as Vectors and Targets for Therapy Jacques Banchereau, PhD Baylor Institute for Immunology Research
2:20 pm - 2:45 pm Amplification of Vaccine-Induced AntiMelanoma T Cell Reactivity by Immunomodulatory Cytokines David Spaner, MD, PhD
Toronto-Sunnybrook Regional Cancer Center
2:45 pm - 3:10 pm Precision Guiding of Cytolytic Tlymphocyte Responses Cornelis Melief, MD Leiden University Medical Centre
18th Annual Meeting Program Schedule
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18th Annual Meeting Program Schedule
Friday, October 31, 2003 — continued
3:10 pm - 3:25 pm Mannose Receptor Antibody-Mediated Antigen Presentation by Human Dendritic Cells Elicits HLA-Restricted Antigen-Specific Anti-Tumor Immunity Venky Ramakrishna, PhD
Medarex Inc.
3:25 pm - 3:40 pm 8-Color Flow Cytometric Analysis of Post-Vaccination gp100 (209-2m) Specific CD8+ T Cells in Melanoma Patients Edwin Walker, PhD
Earle A. Chiles Research Institute
3:40 pm - 3:55 pm Discovery and Characterization of New Antigens for Therapeutic Vaccination Against Breast Cancer Laszlo Radvanyi, PhD
Aventis Pasteur
3:55 pm - 4:15 pm Refreshment Break CONCURRENT SESSION I – Haverford/Baccarat Ballroom 4:15 pm - 6:00 pm Adoptive Immunotherapy Co-Chairs:
Patrick Hwu, MD MD Anderson Cancer Center David Stroncek, MD National Institutes of Health
4:15 pm - 5:00 pm Approaches to Cancer Immunotherapy Based on Breaking Tolerance to Non-mutated Antigens Overexpressed on Metastatic Cancers Steven A. Rosenberg, MD, PhD
National Cancer Institute
5:00 pm - 5:45 pm T-Cell Therapies for EBV Associated Malignancies Malcolm K. Brenner, MD, PhD Baylor College of Medicine
5:45 pm - 6:00 pm FAS Expression Limits the Effector Function of Tumor-Specific T-Cells Rebecca R. Saff Boston University School of Medicine
CONCURRENT SESSION II – Old Georgetown Ballroom 4:15 pm - 6:00 pm Pediatric Oncology Co-Chairs: Paul Sondel, MD, PhD
University of Wisconsin Jon M. Wigginton, MD Center for Cancer Research-National Cancer Institute
4:15 pm - 4:45 pm Allogeneic Hematopoietic Cell Transplants Coupled with Tumor - Reactive Donor Lymphocytes as Cancer Immunotherapy Richard J. O’Reilly, MD
Memorial Sloan Kettering Cancer Center
4:45 pm - 5:15 pm Adoptive Immunotherapy with HyperExpanded Tumor-Reactive T-Cells Gregory E. Plautz, MD Cleveland Clinic Foundation
5:15 pm - 5:30 pm Immunobiology of NKT and NK Cells in Metastatic Neuroblastoma Robert C. Seeger, MD Childrens Hospital Los Angeles
5:30 pm - 5:45 pm IL12 Induced Regression of Orthotopic Neuroblastoma Tumors: Potential Role for Reversal of Intrinsic Mechanisms of Resistance to Tumor Cell Apoptosis Tahira Khan, PhD
National Cancer Institute
CONCURRENT SESSION III – Waterford/Lalique Ballroom 4:15 pm - 6:00 pm Imaging Co-Chairs: Peter L. Choyke, MD
National Institutes of Health-Clinical Center Steven K. Libutti, MD National Cancer Institute, National Institutes of Health
4:15 pm - 4:50 pm Imaging of Angiogenesis with Dynamic Contrast Enhanced MRI Peter L. Choyke, MD National Institutes of Health-Clinical Center
4:50 pm - 5:25 pm Treatment-Induced Anti-Angiogenesis and Apoptosis in Tumors: Imaging of Early Changes Alexei Bogdanov, Jr., PhD
Massachusetts General Hospital
5:25 pm - 6:00 pm Radiolabeled Antibodies in Cancer Chaitanya Divgi, MD Memorial Sloan Kettering Cancer Center
6:00 pm - 6:30 pm iSBTc Members Only Business Meeting Old Georgetown Room
6:30 pm - 7:30 pm
Member/Sponsor Cocktail Reception (Invitation Only) Crystal
Ballroom Foyer
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Saturday, November 1, 2003
7:00 am - 6:00 pm Registration Open – Meeting Room Foyer (Conference Level) 7:00 am - 7:45 am Continental Breakfast in Crystal Ballroom Foyer 7:45 am - 8:00 am Announcements – Crystal Ballroom
KEYNOTE ADDRESS – Crystal Ballroom 8:00 am - 8:45 am Tumor-Associated Macrophages as a Polarized Type II Phagocyte Population: Role in Progression and Therapy
Alberto Mantovani, MD Mario Negri Institute of Pharmacological Research
JOINT SESSION – Crystal Ballroom 8:45 am - 11:30 am Inhibiting of Inflammatory Mediators Co-Chairs: Michael T. Lotze, MD
University of Pittsburgh School of Medicine Marian Nakada, PhD Centocor, Inc.
8:45 am - 9:05 am Inhibiting Inflammatory Cytokines and Chemokines in the Tumour Microenvironment Frances Balkwill, PhD
Cancer Research UK Trans. Oncology Lab
9:05 am - 9:30 am Inhibition of the Growth Promoting Death Signals in Tumor Biology: A Hypothesis Michael T. Lotze, MD
University of Pittsburgh School of Medicine
9:30 am - 9:50 am Functional Activities Mediated by the IL-10 Related Cytokines: IL-22 and IL-26 Raymond Donnelly, PhD
Food and Drug Administration, Center for Biologics Evaluation and Research
9:50 am - 10:15 am The Role of Inflammatory Mediators in Cancer Progression Marian Nakada, PhD Centocor, Inc.
10:00 am - 4:00 pm EXHIBITS OPEN Cabinet/Judiciary Rooms
10:15 am - 10:45 am Refreshement Break 10:45 am - 11:00 am Anti-MCP-1 Monoclonal Antibodies Effectively Inhibit Tumor Angiogenesis and Growth
Li Yan, MD, PhD Centocor, Inc.
11:00 am - 11:15 am Immune Responses to P53 in Patients with Cancer: Elevated Frequencies of Tetramer+P53 Peptide-Specific T-Cells and Regulatory CD4+CD25+ Cells at Tumor Sites Compared to the Peripheral Circulation Andreas Albers, MD, PhD
University of Pittsburgh Cancer Institute
11:15 am - 11:30 am L-Arginine Consumption by Macrophages Modulates the Expression of T-Cell Receptor CD3z Chain in T Lymphocytes Augusto Ochoa, MD
Stanley S. Scott Cancer Center-LSMU
11:30 am - 1:00 pm Poster Session Posters 65-122 (authors must be present) Box lunches will be available in Cabinet/ Judiciary rooms
PRESIDENTIAL SESSION – Crystal Ballroom 1:00 pm - 2:20 pm Presidential Session Michael B. Atkins, MD Beth Israel Deaconess Medical Center
Sponsored by Aventis
1:00 pm - 1:20 pm Reconstitution of Lymphopenic Mice with CD25-Depleted Spleen Cells from Tumor-Bearing Mice, Eliminates Tumor-Induced Suppression, Restores the Tumor-Specific Response to Vaccination and Therapeutic Efficacy of Adoptive Immunotherapy Christian Poehlein, MD Earle A. Chiles Research Institute
1:20 pm - 1:40 pm Vaccination by Genetically Modified Dendritic Cells Expressing the HER-2/ NEU Oncogene Prevents Development of Spontaneous Breast Cancer in Transgenic Mice Yoshio Sakai, MD, PhD
National Cancer Institute
1:40 pm - 2:00 pm Adoptive Transfer of CD8+ T Lymphocytes into Lympho-Depleted Receipients Results in Breaking of Tolerance, Autoimmunity, and Cancer Regression Steven E. Finkelstein, MD
National Institutes of Health-National Cancer Institute
18th Annual Meeting Program
Schedule
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2:00 pm - 2:20 pm Expression Pattern of Chemokine Receptor 6 (CCR6) and CCR7 in Squamous Cell Carcinoma of the Head and Neck Identifies a Novel Metastatic Phenotype Robert L. Ferris, MD, PhD
University of Pittsburgh Cancer Institute
2:20 pm - 3:00 pm Refreshment Break Sponsored by IDM
CONCURRENT SESSION I – Waterford/Lalique Ballroom 3:00 pm - 4:45 pm Cytokines-Polymorphisms Co-Chairs: Martin Howell, PhD
Southampton General Hospital Francesco Marincola, MD National Institutes of Health-Clinical Center
3:00 pm - 3:30 pm The Tumor Necrosis Factor and Interleukin-10 Loci in Colorectal and Breast Cancer Grant Gallagher, PhD
University of Medicine and Dentistry of New Jersey
3:30 pm - 4:00 pm Type I TGF-Beta Receptor Polymorphisms and Breast Cancer Risk: New Data and a Meta-Analysis Elad Ziv, MD
University California-San Francisco
4:00 pm - 4:30 pm Interleukin-10 and Other Cytokine Polymorphism in Melanoma and Prostate Cancer Stephen Chanock, MD
National Cancer Institute
4:30 pm - 5:00 pm Cytokine Gene Polymorphisms and Angiogenesis in Malignant Melanoma and Prostate Cancer Martin Howell, PhD
Southampton General Hospital
CONCURRENT SESSION II – Haverford/Baccarat 3:00 pm - 4:45 pm Angiogenesis Monitoring Workshop Follow-up Co-Chairs:
Raghu Kalluri, PhD Beth Israel Deaconess Medical Center Steven K. Libutti, MD National Cancer Institute, National Institutes of Health
3:00 pm - 3:30 pm Endogenous Inhibitors of Angiogenesis are Tumor Suppressors Raghu Kalluri, PhD Beth Israel Deaconess Medical Center
3:30 pm - 4:00 pm Molecular Diversity and Targeted Therapy Wadih Arap, MD, PhD MD Anderson Cancer Center
Renata Pasqualini, PhD MD Anderson Cancer Center
4:00 pm - 4:15 pm Homing of Dendritic Cells to Lymph Nodes Depends on Self-Produced Angiogenic Factors Christine Odoux, PhD Hillman Cancer Center
4:15 pm - 4:30 pm Anti-VEGF Therapy by Hydrodynamic Delivery Suppresses Growth of Renal Cell Carcinoma that Expresses Multiple Pro-Angiogenic Factors Hiroshi Yazawa, PhD
National Cancer Institute
4:30 pm - 4:45 pm Analysis of Angiogenic Factors in Cultured Cell Supernatants, Sera, and Plasma Using a Multiplexed 9Analyte Angiogenic Array Scott Orencole, PhD
Pierce Biotechnology
CONCURRENT SESSION III – Old Georgetown Ballroom 3:00 pm - 4:30 pm Genomics Co-Chairs: Michael L. Bittner, PhD
Translational Genomics Research Institute Ena Wang, MD National Institutes of Health-Clinical Center
3:00 pm - 3:30 pm Transcriptional Profiles of Dendritic Cells in Response to Inflammatory Stimuli Paola Ricciardi-Castagnoli, PhD
University of Milano-Bioscience
3:30 pm - 4:00 pm Analysis of Expression Profiles Based on Mechanistic Expectations Michael L. Bittner, PhD Translational Genomics Research Institute
4:00 pm - 4:15 pm Quiescent Phenotype of Tumor-Specific CD8 + T Cells Following Immunization Vladia Monsurro, PhD National Institutes of Health
18th Annual Meeting Program
Schedule
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4:15 pm - 4:30 pm Epithelial Growth Factor-Activation Protein, a Novel Target for Cancer Treatment Validated by SiRNA Mediated Gene Knockdown In-Vivo Frank Xie, PhD
Intradigm Corporation
PRESIDENTAL RECEPTION – Crystal Ballroom Foyer 5:00 pm - 6:30 pm Presidential Reception Announcement of Presidential Award Winner
Michael B. Atkins, MD iSBTc President Beth Israel Deaconess Medical Center
18th Annual Meeting Program
Schedule
Sunday, November 2, 2003
7:30 am - 12:00 pm Registration Open – Meeting Room Foyer (Conference Level) 7:30 am - 8:00 am Continental Breakfast in Crystal Ballroom Foyer
JOINT SESSION – Crystal Ballroom 8:00 am - 10:30 am New Agents in Development Co-Chairs: Janice P. Dutcher, MD
Our Lady of Mercy Medical Center Mel Sorensen, MD GlaxoSmithKline Sponsored by Celegene
8:00 am - 8:30 am Phase I Dose Escalation Study to Assess the Safety and Pharmacokinetics of Recombinant Human IL-18 (rhIL-18/ SB485232) Administered as Five Daily Intravenous Infusions in Adult Patients with Solid Tumors Mohammed Dar, MD
GlaxoSmithKline
8:30 am - 9:00 am Update on the Clincial Development of GSK’s Dual ErbB Kinase Inhibitor Mark S. Berger, MD GlaxoSmithKline
9:00 am - 9:30 am VEGF Trap: A Novel VEGF Blocker with Potent Anti-Tumor Effects George D. Yancopoulos, MD, PhD Regeneron Pharmaceuticals, Inc.
9:30 am - 9:45 am The Proteasome Inhibitor Velcade™ Sensitizes Tumor Cells to Trail-Mediated Apoptosis Thomas J. Sayers, PhD
National Cancer Institute
9:45 am - 10:00 am Efficacy and Tolerability of Interleukin21 in a Mouse Model of Metastatic Melanoma Steve D. Hughes, PhD
ZymoGenetics
10:00 am - 10:15 am A Phase II Study in Advanced Renal Cell Carcinoma of ABR-214936 (Anatumomab Mafenatox) Tumour Targeted Superantigen Therapy Robert E. Hawkins, MD, PhD
University of Manchester
10:15 am - 10:30 am Update on the Evolution of the IMiD Jerome Zeldis, MD, PhD Celgene Corporation
Saturday, November 1, 2003 — continued
Program printing sponsored by
iSBTc Presidential Award Receipients
1991 – Pittsburgh, PA Judith Kantor, PhD – National Cancer Institute – Bethesda, MD
1992 – Williamsburg, VA Carol A. Nieroda, MD – National Cancer Institute – Bethesda, MD
1993 – Nashville, TN David G. Maloney, MD, PhD – Stanford University – Stanford, CA
1994 – Napa, CA Laurence Zitvogel, MD, PhD – University of Pittsburgh – Pittsburgh, PA
1995 – Williamsburg, VA Jon M. Wigginton, MD – National Cancer Institute – Frederick, MD
1996 – Washington, DC Carmen Scheibenbogen, MD – University Hospital Benjamin Franklin Free University, Berlin – Berlin, Germany
1997 – Pasadena, CA Pia M. Challita-Eid, PhD – University of Rochester Cancer Center – Rochester, NY Tadashi Osaki, MD, PhD – University of Pittsburgh – Pittsburgh, PA
1998 – Pittsburgh, PA Clemens Esche, MD – University of Pittsburgh – Pittsburgh, PA
1999 – Boston, MA Roopa Srinivasan, PhD – Memorial Sloan Kettering Cancer Center – New York, NY
2000 – Seattle, WA Robbie Malliard – University of Pittsburgh – Pittsburgh, PA
2000 – Berlin, Germany Annette Paschen, MD – University Clinics of Mannheim – Mannheim, Germany
2001 – Bethesda, MD Julia A. Coronella, PhD – University of Arizona – Arizona Cancer Center – Tucson, AZ
2002 – San Diego, CA Erin B. Dickerson, PhD – Univ. of Wisconsin-Madison – School of Veterinary Medicine – Madison, WI
2003 – Find out at the Presidential Reception Saturday at 5:30 – Crystal Ballrrom Foyer
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Annual Meeting Faculty
Wadih Arap, MD, PhD MD Anderson Cancer Center Houston, TX Michael B. Atkins, MD Beth Israel Deaconess Medical Center Boston, MA Frances Balkwill, PhD Cancer Research UK Trans. Oncology Lab London, United Kingdom Jacques Banchereau, PhD Baylor Institute for Immunology Research Dallas, TX Mark S. Berger, MD GlaxoSmithKline Collegeville, PA
Neil Berinstein, MD Aventis Pasteur Toronto, Canada Michael L. Bittner, PhD Translational Genomics Research Institute Phoenix, AZ Alexei Bogdanov, Jr., PhD Massachusetts General Hospital Charlestown, MA Malcolm K. Brenner, MD, PhD Baylor College of Medicine Houston, TX Paola Ricciardi-Castagnoli, PhD University of Milano-Bioscience Milano, Italy Stephen Chanock, MD National Cancer Institute Gaithersburg, MD Peter L. Choyke, MD National Institutes of Health Bethesda, MD
Mohammed Dar, MD GlaxoSmithKline Research Triangle Park, NC Chaitanya Divgi, MD Memorial Sloan Kettering Cancer Center New York, NY Raymond Donnelly, PhD Food and Drug Adminstration Center for Biologics Bethesda, MD Janice P. Dutcher, MD Our Lady of Mercy Medical Center Bronx, NY
Grant Gallagher, PhD University of Medicine and Dentistry of New Jersey Newark, NJ Veronika Groh-Spies, MD Fred Hutchinson Cancer Research Center Seattle, WA Jenny Gumperz, PhD Brigham and Women’s Hospital Boston, MA Martin Howell, PhD Southampton General Hospital Southhampton, United Kingdom Patrick Hwu, MD MD Anderson Cancer Center Houston, TX
Raghu Kalluri, PhD Beth Israel Deaconess Medical Center Boston, MA Steven K. Libutti, MD National Cancer Institute Bethesda, MD Eric O. Long, PhD National Institutes of Health Rockville, MD Michael T. Lotze, MD University of Pittsburgh School of Medicine Pittsburgh, PA Alberto Mantovani, MD Mario Negri Institute of Pharmacological Research Milan, Italy Francesco Marincola, MD National Institutes of Health Bethesda, MD Cornelis Melief, MD Leiden University Medical Centre Leiden, Netherlands Marian Nakada, PhD Centocor Inc. Malvern, PA Richard J. O’Reilly, MD Memorial Sloan Kettering Cancer Center New York, NY John R. Ortaldo, PhD National Cancer Institute Frederick, MD
Drew Pardoll, MD, PhD Johns Hopkins University School of Medicine Baltimore, MD Peter Parham, PhD Stanford University School of Medicine Stanford, CA Renata Pasqualini, PhD MD Anderson Cancer Center Houston, TX Gregory E. Plautz, MD Cleveland Clinic Foundation Cleveland, OH Steven A. Rosenberg, MD, PhD National Cancer Institute Bethesda, MD Robert C. Seeger, MD Keck School of Medicine Los Angeles, CA Paul Sondel, MD, PhD University of Wisconsin Madison, WI Mel Sorensen, MD GlaxoSmithKline Collegeville, PA David Spaner, MD, PhD Toronto-Sunnybrook Regional Cancer Center Toronto, Canada David Stroncek, MD National Institutes of Health Bethesda, MD Ena Wang, MD National Institutes of Health Bethesda, MD Jon M. Wigginton, MD Center for Cancer Research-National Cancer Institute Frederick, MD George D. Yancopoulos, MD, PhD Regeneron Pharmaceuticals, Inc. Tarrytown, NY Elad Ziv, MD University California-San Francisco San Francisco, CA Kathryn C. Zoon, PhD Food and Drug Adminstration Center for Biologics Evaluation and Research Bethesda, MD
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Andreas Albers, MD, PhD University of Pittsburgh Cancer Institute Pittsburgh, PA
Robert L. Ferris, MD, PhD University of Pittsburgh Cancer Institute Pittsburgh, PA
Steven Eric Finkelstein, MD National Cancer Institute Bethesda, MD
Robert E. Hawkins, MD, PhD Paterson Institute for Cancer Research Manchester, United Kingdom
Steve D. Hughes, PhD ZymoGenetics Seattle, WA Tahira Khan, PhD National Cancer Institute Frederick, MD
Hillary Lum University of Wisconsin Medical School Madison, WI
Robbie B. Mailliard University of Pittsburgh Cancer Center Pittsburgh, PA
Vladia Monsurro, PhD National Institutes of Health Bethesda, MD
Augusto Ochoa, MD Stanley S. Scott Cancer Center-LSMU New Orleans, LA
Christine F. Odoux, PhD Hillman Cancer Center Pittsburgh, PA
Scott Orencole, PhD Pierce Biotechnology Woburn, MA
Christian Poehlein, MD Earle A. Chiles Research Institute Portland, OR
Laszlo Radvanyi, PhD Aventis Pasteur Toronto, Canada
Venky Ramakrishna, PhD Medarex, Inc. Bloomsbury, NJ
Rebecca R. Saff Boston University School of Medicine Boston, MA
Oral Abstract Presenters
Yoshio Sakai, MD, PhD National Cancer Institute Bethesda, MD
Thomas J. Sayers, PhD National Cancer Institute Frederick, MD
Nikola L. Vujanovic, MD, PhD University of Pittsburgh Pittsburgh, PA
Edwin Walker, PhD Earle A. Chiles Research Institute Portland, OR
Frank Xie, PhD Intradigm Corporation Rockville, MD
Li Yan, MD, PhD Centocor, Inc. Radnor, PA
Hiroshi Yazawa, PhD National Cancer Institute Frederick, MD
Jerome Zeldis, MD,PhD Celgene Corporation Warren, NJ
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iSBTc Membership Information
History of the International Society for Biological Therapy of Cancer (iSBTc) The Society for Biological Therapy was founded in 1984 with 40 charter members. The Society currently has over 500 members consisting primarily of MDs, PhDs, RNs, and corporate representatives. Scientific and business meetings have been held annually since the first Annual Meeting of SBT in 1986. At the 2002 business meeting held November 9, 2002, the SBT membership voted to officially change the name of the Society and it thus became the International Society for Biological Therapy of Cancer (iSBTc).
New Members
Goals and Objectives of iSBTc The purpose and mission of the International Society for Biological Therapy of Cancer (iSBTc) is to bring together those individuals actively involved in the preclinical and clinical investigation of biological agents in the treatment of cancer. The objectives of the Society are to:
Develop and promote educational programs, including an annual meeting, which advance and promote the Society’s purpose and mission
Develop and promote training and credentialing programs in biological treatment of cancer
Collaborate with and support other scholarly societies and organizations for the purpose of advancing and promoting iSBTc’s purpose and mission
Conduct clinical trials with biological agents in the treatment of cancer and create and support consortia and alliances with other organizations pursuing similar trials
Engage in such other educational, training and informational activities as will further or promote the Society’s purpose and mission
Benefits of iSBTc Membership Subscription to Journal of Immunotherapy, the official journal of iSBT. (The cost of the Journal of the iSBTc is included in annual membership dues)
Early registration opportunities for Society meetings
Reduction in Annual Meeting registration fees
Sponsorship of abstracts for presentation at Annual Meetings, with eligibility for Presidential Award
Annual Directory of Members
Annual Meeting Program & Abstracts
iSBTc website: www.isbtc.org
Membership Application Requirements and Annual Dues Fellow Membership ($195 annual dues) is available only to MDs and PhDs who have been iSBTc members of any class, current in dues for at least 2 years. Fellowship includes the right to vote and hold office.
Regular Membership ($195 annual dues) requires the applicant to have a MD or PhD in a biological science or the equivalent and be an active, bona fide representative of the international scientific community with a specialty or interest in a field related to the biological therapy of cancer. Regular membership includes the right to vote and hold office.
Associate Membership ($140 annual dues) requires the applicant to have a degree and a specialty or interest in a field related to the biological therapy of cancer. Associate membership includes allied health professionals, physician assistants, nurse practitioners, technicians and other areas related to the biological therapy of cancer. Associate membership does not include the right to vote or hold office.
Affiliate Membership ($195 annual dues) is available to individuals active in the discovery and translation of biological therapy of cancer who do not otherwise meet the requirements for Fellow, Regular or Associate membership. Affiliate membership does not include the right to vote or hold office.
Corporate Membership ($275 annual dues) is available to one representative from a company active in the discovery and translation of biological agents. Corporate membership includes the right of one vote per corporation. Corporate members are not eligible to hold office.
Memberships may and shall be transferred from one class to another by action of the iSBTc Board of Directors.
Membership Application Instructions 1. Check the membership category for which you are applying.
2. Fill in the appropriate contact information.
3. Have this form or a copy signed by the iSBTc member who is nominating you or, in lieu of a member’s signature, please list two individuals (and their complete contact information) who are familiar with your work.
4. Return application form, with a copy of your curriculum vitae or educational resume and application fee to the iSBTc office.
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Please check the membership category you are applying for:
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Application Fee $50.00 - the remainder of your dues will be invoiced upon your acceptance
An application fee of $50 is required to complete this application. Upon approval for membership, this $50 application fee will be credited toward annual membership dues and the remaining dues balance will be invoiced.
The Membership Committee submits applications to the iSBTc Board of Directors four times per year, in February, May, August and November (or at the Annual Meeting in Fall). All members are elected by a majority vote of the iSBTc Board of Directors.
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Return this form to: iSBTc 611 E. Wells St., Milwaukee, WI 53202 Phone: 414/271-2456 Fax: 414/276-3349 E-mail: info@isbtc.org Web: www.isbtc.org
iSBTc Membership Application
Application January, 2003
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iSBTc 2003 Exhibitor Listing
Aastrom Biosciences, Inc. Booth Number: 15 24 Frank Lloyd Wright Drive Ann Arbor, MI 48105
Affymetrix Booth Number: 14 3380 Central Expressway Santa Clara, CA 95051
Affymetrix is the market leader in creating break-through tools that are driving the genomic revolution. Affymetrix offers an expanding portfolio of integrated products and services, including its integrated GeneChip platform, to address growing markets focused on understanding the relationship between genes and human health. In addition to the GeneChip technology platform which includes the GeneChip arrays, Affymetrix will be featuring advances in instrument design, automation and data management tools for genomics research.
Biovest International 8500 Evergreen Blvd. Minneapolis, MN 55433
Cell Technology, Inc. Booth Number: 11 8980 Old Annapolis Columbia, MD 21045
CTI (Cell Technology, Inc.) provides secure repository services and retrieval and distribution support to the biomedical R&D sector in North America. CTI is also the North American distributor of lab kits and automated imaging equipment marketed by AID (AutoImmun Diagnostika GmbH), a company based in Strassberg, Germany. AID’s EliSpot Readers, which have been sold in over twenty countries, have become important tools for analyzing potential AIDS and cancer vaccines.
Centocor Booth Number: 3 200 Great Valley Parkway Malvern, PA 19355
Centocor is a leading biopharmaceutical company that creates, acquires and markets cost-effective therapies that yield long-term benefits for patients and the healthcare community. Centocor’s products, developed primarily through monoclonal antibody technology, help physicians deliver innovative treatments to improve human health and restore patients’ quality of life. Centocor is a wholly owned subsidiary of Johnson & Johnson, the worldwide manufacturer of healthcare products.
Chiron Corporation Booth Number: 9 4560 Horton Street Emeryville, CA 94608-2916
Chiron Corporation, headquartered in Emeryville, California is a leading biotechnology company that participates in three global healthcare markets: biopharmaceuticals, vaccines and blood testing. The company is applying an integrated scientific approach to the development of innovative products for preventing and treating cancer and infection. For more information about Chiron, visit the website at http:// www.chiron.com
Food & Drug Administration Booth Number 5 5600 Fishers Lane Rockville MD 20857-0001
The Food and Drug Administrations’ Center for Biologics Evaluation and Research (CBER), one of six centers within FDA, is responsible for the regulation of biologically-derived products, including blood intended for transfusion, blood components and derivatives, vaccines and allergenic extracts, and tissue, cell and gene therapy products. Please stop by the CBER booth to obtain regulatory information regarding biological therapies.
Genetech BioOncology Booth Number: 10 1 DNA Way South San Francisco, CA 94080-4990
Genitope Corporation Booth Number: 4 525 Penobscot Drive Redwood City, CA 94063
ImmunoBiosys, Inc. Booth Number: 16 P.O. Box 86087 Montgomery Village, MD 20886-6087
The Bioreader®, for Elispot, Plaque, CFU and Soft-Agar assays, is widely used to read all types of multiwell microtiter plates (e.g., transparent, opaque, filter). Combining a high-resolution camera (monochrome or color) and proprietary 3-D illumination results in higher sensitivity and sharpness, no risk of counting reflected “phantom image” spots and improved quantification of cytokine activity by measurement of total optical density. Find out how our advanced hardware design features and extensive, flexible software may facilitate your plate reading and analysis.
National Cancer Institute Booth Number: 6 & 7 Office of Cancer Complementary & Alternative Medicine 6116 Executive Drive Bethesda, MD 20892
Partek Incorporated Booth Number: 20 4 Research Drive Suite 100 St. Charles, MO 63304
Partek develops and markets interactive statistical analysis and visualization software tools and consulting services. Partek’s products have been widely adopted for use with gene expression data. www.partek.com
Exhibit Hall Hours – Cabinet/Judiciary Ballroom
Friday, October 31 10:00 am-5:00 pm Saturday, November 1 10:00 am-4:00 pm
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iSBTc 2003 Exhibitor Listing
Pel-Freez Booth Number: 2 9099 N. Deerbrook Trail Milwaukee, WI 53223
Pel-Freez Clinical Systems, LLC is a global biotechnology company that focuses on human diagnostics. Pel-Freez Clinical Systems’ develops, manufactures and market a comprehensive line of molecular and serologic diagnostic kits for bone marrow and solid organ transplantation, disease association and research. Pel-Freez Clinical Systems is a world leader in the HLA typing market, providing over 150 products to customers in more than 70 countries.
PeproTech, Inc. Booth Number: 1 5 Crescent Avenue PO Box 275 Rocky Hill, NJ 08553
Using state-of-the-art facilities, proprietary technologies and devoted personnel, PeproTech has been successful in developing an extensive line of recombinant human, murine and rat cytokines as well as a complementary line of monoclonal and polyclonal antibodies.
Schering Oncology Biotech Booth Number: 8 2000 Galloping Hill Road Kenilworth, NJ 07033
Schering Oncology/Biotech is a research based pharmaceutical company with headquarters in Kenilworth, NJ. Visit the Schering Oncology/Biotech booth to learn more about INTRON(r) A (Interferon alfa 2b, recombinant) Injection.
Seppic, Inc. Booth Number: 12 30 Two Bridges Road, Suite 210 Fairfield, NJ 07004
Seppic manufactures two adjuvants specifically for human therapeutic vaccines. Our Montanide ISA 51 and Montanide ISA 720 are emulsion based systems that have been used in numerous clinical trials. Both of these adjuvants are “ready to use” and only require the addition of antigenic media and mixing to from the final dosage form.
Exhibit Hall — Judiciary Suite
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Poster Session and Exhibit Hours
Posters 1-64 Friday, October 31 12:00 pm-1:30 pm
Posters 65-122 Saturday, November 1 11:30 am-1:00 pm
Exhibits Open Friday, October 31 10:00 am-5:00 pm Saturday, November 1 10:00 am-4:00 pm
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Oral Abstracts
Natural Killer Cells & Innate Immunity
Immunogenetics, Diversity and Clinical Relevance of Killer Cell Immunoglobulin-like Receptors Peter Parham, Stanford University, Stanford, CA
Natural killer (NK) cells are lymphocytes of innate immunity that respond to infection by cytokine secretion and cytolytic acti vity. Among the many different receptors on NK cell surfaces are ones that engage major histocompatibility complex (MHC) class I molecules and structurally related ligands. Human NK cells express both lectin-like receptors and immunoglobulin-like receptors with specificity for HLA class I. Population studies in humans and comparison of humans with the closest primate relatives demonstra te that the killer immunoglubulin-like receptors (KIR) comprise a highly variable and rapidly-evolving family of genes, whereas ge nes encoding the lectin-like receptors are relatively conserved. Within the circulation individual NK cells express different combi nations
of KIR and lectin-like receptors, producing an NK cell repertoire. As a consequence of KIR variability, unrelated individuals u sually have different combinations of KIR genes and establish different NK cell repertoires. These differences likely provide advantag e for populations in facing infection, in a way analogous to that proposed for HLA class I and II. In development of the NK cell repe rtoire the HLA class I type has a minor selective effect, whereas in the periphery it determines which receptors can interact with a s elf HLA class I ligand. Of bone marrow and stem-cell transplants performed between HLA-matched siblings 75% are performed across a KIR mismatch, and for transplants between unrelated donors the number is close to 100%. After transplantation we find that one grou p of patients recapitulate the NK cell repertoire of the donor while in another group the expression of KIR was slow to recover but eventu-
ally reconstituted with donor type. Association of KIR difference with clinical outcome in transplantation is being assessed.
Significance of the Human NKG2D Receptor and its Tumor-Associated Ligands Veronika Groh, Thomas Spies, Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA
The NKG2D receptor activates natural killer (NK) cells and costimulates CD8 T cells upon engagement by ligands that include the MHC class I homologs MICA and MICB, which have no role in antigen presentation but function as signals of cellular distress. Th ese molecules are absent from most cell types and tissues but are frequently expressed in epithelial tumors, suggesting that their binding to NKG2D should promote anti-tumor NK and T-cell responses. In vivo mouse models indicate that NKG2D may promote NK cell and
T cell-mediated tumor rejection. However, this may not be the case with human epithelial tumors. The presence of MIC on many progressing tumors including breast, lung, gastric, renal, colon, ovarian and prostate carcinomas and melanomas suggests that M IC or NKG2D could be functionally impaired, thus promoting immune evasion. We have shown that binding of MIC induces endocytosis and degradation of NKG2D and that NKG2D expression is markedly reduced on large proportions of tumor-infiltrating and matched peripheral blood T cells from cancer patients. This systemic deficiency is associated with circulating tumor-derived soluble MI CA, which causes the down regulation of NKG2D. As a result, the responsiveness of tumor antigen-specific effector T cells is severe ly impaired. We are exploring whether soluble MIC can be used as a marker for the diagnosis or prognosis of cancer. Because MIC is a broadly distributed epithelial tumor marker, additional studies are aimed at exploring whether antibody-mediated cross linking of tumor and antigen-presenting cells may enhance cross presentation of tumor-associated antigens and T-cell priming.
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Oral Abstracts
CD1d-restricted ‘NKT’ Cells and Myeloid Dendritic Cell IL-12 Production Jenny Gumperz, Fred Hutchinson Cancer Research Center, Seattle, WA
CD1d-restricted T cells (or “NKT” cells) recognize lipid and glycolipid antigens presented by CD1d molecules expressed on B cel ls, monocytes, macrophages, and dendritic cells (DCs). These unique T cells rapidly and potently produce both Th1 and Th2-type cytokines upon recognition of the unusual synthetic glycolipid antigen ±-galactosylceramide (± -GalCer), and can also demonstra te modest cytokine secretion in response to self antigens. CD1d-restricted T cells have been implicated both in preventing the dev elopment of autoimmune diseases and in promoting effective Th1-inflammatory responses in vivo. Their role in anti-tumor responses h as been difficult to define. In some cases they have been shown to be important for successful tumor rejection and tumor immunosurveillance, whereas, paradoxically, in other cases they appear to suppress effective anti-tumor responses. Our results suggest these contrasting effects may be due to the malleable nature of the interaction between CD1d-restricted T cells and myeloid DCs . We have found that upon recognizing self antigens presented by CD1d molecules on immature DCs, CD1d-restricted T cells induced DC maturation. The resulting DCs produced high levels of IL-10 and appeared to have a tolerogenic pheontype, as they stimulated na ive T cells to proliferate but not to produce IFN³. When CD1d-restricted T cells were exposed to immature DCs presenting the strong antigen ±-GalCer, DC maturation also occurred, but the resulting mature DCs had an immunostimulatory phenotype, producing high levels of IL-12 and potently activating both proliferation and IFN³ production by naive T cells. Exposure of CD1d-restricted T cells to IL-12 resulted in marked amplification of their IFN³ production in response to self antigen recognition, suggesting that inflam matory
conditions could also influence the outcome of their interactions with immature DCs. Together, these results suggest a model in which, depending on the context, CD1d-restricted T cells can promote either tolerogenic or immunostimulatory effects on other T cells via their interactions with DCs.
Hydrodynamic IL-2 cDNA Injection: Modulation of NK Innate Function John R. Ortaldo, NCI-NIH — Frederick Cancer R&D Ctr., Frederick, MD
NK Cells Provide Dendritic Cell-Mediated Help for Th1 and CTL Responses: “Two-Signal” Requirement for the Induction of NK Cell Helper Function Robbie Malliard 1, Young-Ik Son1, Adam Giermasz1, Walter Storkus1, Pawel Kalinski1. 1Surgery, University of Pittsburgh Cancer Institute, Pittsburgh, PA.
Dendritic cells (DCs) and Natural Killer (NK) cells have been shown to exchange bi-directional activating signals. We observed that NK cells induce DC maturation into stable type-1 polarized DC (DC1), characterized by elevated ability to produce IL-12 and by strongly-increased Th1- and CTL-inducing functions. The induction of DC1s, both in direct DC-NK cell co-cultures and in transwe ll models, critically depends on IFN-g and TNF-a secretion. However, the NK-induced DC1 phenotype is significantly more pronounced than the one induced by recombinant IFN-g and TNF-a, suggesting the involvement of additional factors. The induction of DC1mediated immunoregulatory function in resting NK cells requires additional activating signals, compared to the induction of the ir killer function. While the recognition of target cells (K562) effectively induces NK cell cytotoxicity, the induction of the DC activat-
ing/polarizing activity of NK cells requires co-stimulatory signals from type-1 IFNs, products of virally-infected cells. There fore, in addition to their “killer” function, NK cells have a novel DC1-mediated “helper” role, induced under more stringent conditions. The currently demonstrated “helper” activity of NK cells may support the development of Th1- and CTL-dominated type-1 immunity against intracellular pathogens, and may be utilized to enhance the effectiveness of cancer immunotherapy.
Natural Killer Cells & Innate Immunity — continued
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Oral Abstracts
Critical Role of TNF Family Ligands in NK Cell-Dendritic Cell Interaction Valeria Makarenkova1, Petar Popovic1, Ganwei Lu1, Nikola Vujanovic 1. 1Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA.
NK cells and dendritic cells (DC) are essential cellular components of the innate immunity, which mediate acute inflammation an d anticancer immune functions. Recent studies have shown that NK cells and DC coordinately interact via direct cell-cell contact and secreted mediators, and reciprocally promote NK cytolytic activity and DC maturation. Mounting evidence suggests that this earl y cellular “cross talk” is critically important to the quality and magnitude of the evolving adaptive immune response. We have pr eviously shown that NK cells and DC constitutively express multiple transmembrane TNF family ligands and corresponding TNF family receptors suggesting that these cells might be able to interact and collaborate via the engagement of TNF family molecules. In the present study, we investigated the role of TNF family molecules in NK cell-DC interaction. We showed that TNF family ligands of either cell type cooperatively mediated death of cancer cells and generation of cellular fragments containing tumor antigens. I n addition, using blockade with antibodies and/or gene deficiency strategies to disrupt the engagement of TNF family molecules, w e determined that engagements of TNF-TNFR2, CD40L-CD40, and LT-a1b2-LT-bR ligand-receptor pairs were critical to NK cell-DC interaction and reciprocal increases in secretion of IL-12 and IFN-g, expression of TNF family ligands, tumoricidal activities via TNF family ligands and perforin/granzyme, and helper function in generation of cancer-specific cytolytic T lymphocytes. These findi ngs indicate that NK cell-DC interaction via TNF family molecules might be important to optimal functioning of both innate and adap tive antitumor immunities, and efficient immune recognition and elimination of cancer.
T Cell Independent Control of Murine Neuroblastoma by CD40 Monoclonal Antibody Therapy Hillary E Lum1, Alexander L Rakhmilevich1, Ilia N Buhtoiarov 1, Brian E Schmidt1, Paul M Sondel1. 1Human Oncology and Comprehensive Cancer Center, University of Wisconsin, Madison, WI.
Activation of immune effector cells via CD40 ligation is not limited to T cells. We have previously shown a role for natural ki ller (NK) cells in the antitumor effects of CD40 ligation. In addition, the presence of CD40 molecules on the surface of macrophages suggests another potential mechanism of antitumor activity. In a model of murine neuroblastoma, progression of NXS2 subcutaneou s tumors was significantly limited by agonist CD40 monoclonal antibody (CD40 mAb) therapy in both immunocompetent (A/J) and
SCID mice. NK cell activity was enhanced following CD40 mAb administration. However, a significant antitumor effect of CD40 mAb treatment was also observed in SCID/beige mice demonstrating effective tumor control in the absence of functional T and NK cell cytotoxicity. This effect of CD40 mAb treatment was similar to the antitumor effect of lipopolysaccharide (LPS), a known macrophage-activating agent. In vivo CD40 mAb-activated murine macrophages had a limited tumoristatic effect in vitro that requ ired LPS triggering for increased antitumor activity against NXS2 cells. We conclude that CD40 mAb immunotherapy against the NXS2 neuroblastoma can be effective in the absence of T cells by activating innate immune effector cells including macrophages as we ll as NK cells.
This work was supported by grants from the MACC foundation and NIH (RO1 CA87025-01). INB is supported by a fellowship grant for beginning investigators from the UICC-American Cancer Society.
Natural Killer Cells & Innate Immunity — continued
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Oral Abstracts
Dendritic Cells & Vaccines
DC – T Cell Cross Talk Determines the Balance between Immune Tolerance and Activation Drew Pardoll, Johns Hopkins Univ. School of Medicine, Baltimore, MD
Dendritic Cells as Vectors and Targets for Therapy
Jacques Banchereau, Gaetan Jego, Sophie Paczesny, Joseph W. Fay, Madhav Dhodapkar, Ralph Steinman, Virginia Pascual and A. Karolina Palucka, Baylor Institute for Immunology Research, Dallas, TX
Dendritic cells initiate and control immune responses. As such they are considered essential targets in vaccine development. Ho wever DCs comprise multiple subsets with different functions. Thus clarifying their role requires multiple approaches including to as sess their functions in ex-vivo protocols. Early trials in humans have shown the safety of cancer antigens-loaded DCs as well as som e clinical and immune responses. However, many issues remain to be addressed including the choice of the DC subset to be administered and the way to generate it. The most popular way is to culture blood monocytes with GM-CSF and IL-4, which yield a unifor m population of immature DC resembling interstitial DCs (intDCs). This contrast with hematopoietic stem cells that, when cultured with GM-CSF and TNF, yield preparations that include intDCs as well as Langerhans cells (LCs). While GM-CSF/IL-4 induced DCs require additional maturation factors, CD34-DCs do not as they are generated in the presence of TNF alpha, a DC activation fact or. We have vaccinated 18 HLA A*0201+ patients with stage IV melanoma with CD34-HPC-derived DCs pulsed with six Ags: influenza
matrix peptide (Flu-MP), KLH, and peptides derived from the four melanoma Ags: MART-1/Melan A, gp100, tyrosinase and MAGE3. A single DC vaccination was sufficient for induction of 1) KLH specific responses in 6 patients, 2) Flu-MP-specific response s in 8 patients, and 3) tumor specific effectors to > 1 melanoma antigen in 5 patients. None of these 5 patients showed early disease progression. Only 1/6 patients with rapid KLH-response experienced early disease progression. Rapid and slow Flu-MP responders did not
differ with regard to disease progression. Analysis at 10 weeks (after 4 vaccinations) revealed an immune response to control a ntigens in 16/18 patients. An enhanced immune response to 1 or more melanoma antigens (MelAg) was seen in these 16 patients. The 2 patients failing to respond experienced rapid tumor progression. 6/7 patients with immunity to 2 or less MelAg had progressive disease 10 weeks after study entry, in contrast to tumor progression in only 1/10 patients with immunity to > 2 MelAg. The tumo r
immunity score correlated with clinical outcome. Eleven patients received 4 additional “boosting” injections. Analysis of overa ll survival from study entry revealed that 12/18 patients were alive at year 1 and 9/18 patients were alive at year 2. Overall sur vival from study entry as well as the time to disease progression were related to the level of vaccine-specific immune responses detected at 10 weeks, i.e., after the initial 4 injections, as measured by 1) the magnitude, i.e. the number of melanoma Ags-specific IFN gamm a ELISPOTS, and 2) the breadth, i.e., the number of melanoma antigens to which T cells respond.
Since tumor immunotherapy targets autologous antigens we can learn from systemic autoimmunity such as SLE. Until recently SLE has been viewed mainly as a B cell disease resulting from altered T/B cell interactions. The recognition of the fundamental rol e of dendritic cells (DCs) in the control of tolerance and immunity led to the hypothesis that SLE may be driven through unabated DC activation. We have recently uncovered the role of DC subsets and one of their products, IFN-a, in the pathophysiology of SLE. CD14+ monocytes isolated from SLE patients blood, but not those from healthy individuals, act as DCs. Their activation is drive n by
circulating IFN-a that may come from one of the DC subsets, i.e., plasmacytoid DCs that infiltrate SLE skin lesions. Though onl y a fraction of active SLE patients show circulating IFN-a, blood mononuclear cells from all of them display an IFN-? signature. Fi nally, depletion of pDCs from human blood mononuclear cells abrogates the secretion of specific and polyclonal IgGs in response to Influenza virus. Furthermore, purified pDCs triggered with virus induce CD40-activated B cells to differentiate into plasma cel ls. Two
pDCs cytokines act sequentially, with IFN-a/b generating non-Ig secreting plasma blasts and IL-6 inducing their differentiation into Ig-secreting plasma cells. These plasma cells display the high levels of CD38 found on tissue plasma cells. Thus, pDCs are crit ical in generation of plasma cells and antibody responses and should be targeted in the development of vaccines.
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Oral Abstracts
Amplification Of Vaccine-Induced Anti-Melanoma T Cell Reactivity By Immunomodulatory Cytokines
David E. Spaner 1,3,4, Teresa Petrella 3,4, E. Umit Bagriacik2, Mark de Benedette2, Neil Berinstein 2,3,4, Ileana Elias 2, Igor Astasturov 1, 1.Division of Molecular and Cellular Biology, Research Institute, Sunnybrook and Women’s College Health Sciences Center, Toronto, Canada, M4N 3M; 2. Cancer Vaccine program, Aventis-Pasteur, Toronto, Canada, M4N 3M5; 3. Toronto-Sunnybrook Regional Cancer Center, Toronto, Canada, M4N 3M5; 4. Dept. of Medicine, University of Toronto, Toronto, Canada, M4N 3M5; 5. Dept. of Radiology,
Sunnybrook and Women’s College Health Sciences Center, Toronto, Canada, M4N 3M5.
Cancer vaccines are potentially of therapeutic benefit to patients with tumors that are incurable with conventional chemotherap y. A problem with current vaccines (made with defined tumor antigens that are also self-antigens) is that the relatively weak respon ses of vaccine-activated T cells are not maintained for long enough to give therapeutically meaningful results. We administered high d ose Interferon-±2b (IFN-±) (HDI) (20x106 U/m2) for one month to 7 high-risk melanoma patients who had been treated previously with a
vaccine based on immunodominant HLA-A*0201 binding epitopes of the melanoma antigen, gp100. HDI recalled gp100-reactive T cells in the 4 patients who had developed transient immunological responses to the vaccines, but not in the remaining patients in whom a previous response was not detectable. In two of these patients, treatment with HDI resulted in the disappearance of meta static lesions, even though IFN-± had been used for therapeutic purposes before vaccination. Moreover, only the population of gp100-
reactive T cells recalled by HDI was able to kill gp100-expressing tumor targets. IFN-± was found to upregulate the expression of CD80 and CD86 on primary tumor samples. These results suggest that HDI recalls previously activated tumor-reactive T cells that are able to become potent killers (possibly by regulating the expression of costimulatory molecules on residual tumor cells) and al so suggest a strategy to maintain anti-tumor responses initiated by cancer vaccines.
Precision Guiding of Cytolytic T-lymphocyte Responses
Cornelis JM Melief, Hélène Dumortier, Sander Zwaveling, Danita Schuurhuis, Geertje van Mierlo, Jan Paul Medema, Ferry Ossendorp, Sjoerd van der Burg, Rienk Offringa, Leiden University Medical Center Leiden, The Netherlands
Molecular triggers of DC activation sufficient for induction of CD8+ CTL responses include agonistic CD40 antibody or ligands o f Toll like receptors such as LPS (TLR4 ligand) or CpG (TLR9 ligand). In natural immune responses specific CD4 cells, reactive wi th peptide antigens presented by MHC class II molecules on DC, can also drive maturation of immature DC to the mature DC state required for CD8+ CTL response induction. CD4+ T helper cells to a large extent operate through upregulation of CD40L which the n interacts with CD40 on DC to cause the required DC activation. Important cognate interactions for full CD8+ CTL induction by activated DC are CD80/CD86 on the DC, costimulating CD28 on the CD8 cells. For maintenance and full expansion of CD8+ T cells, interaction of 4-1 BBL (another member of the TNF(R) family) on DC with 4-1 BB on CD8+ CTL is also important. In the absence of CD80/CD86 costimulation, the 4-1 BBL -> 4-1 BB interaction appears to be inactive. Thus proper induction, expansion and maintenance of CD8+ CTL responses involve delicate interactions between CD4+ T-cells, DC and CD8+ T-cells involving several members of the TNF(R) family, including as signal transduction molecules CD40 on DC and 4-1 BB as well as CD27 on CD8+ CTL precursors. Recently we obtained conclusive evidence that immature DC loaded with antigen cause T-cell division but not T-cell effect or cell induction, nor T-cell survival in appreciable numbers. LPS stimulated DC, in contrast, stimulated vigorous CD8+ CTL responses i n vivo. Such CD8+ effector cells showed loss of CD62L and CCR7 lymphoid homing receptors, compatible with their migration into blood and parenchymal tissue in large numbers.
We recently investigated the conditions for optimal therapeutic CD8+ CTL induction by long peptide vaccins against human papillomavirus induced mouse tumors. The 32-35 amino acid long peptides were given SC in IFA or in CpG 1826 adjuvant. Powerful therapeutic CTL induction by single peptide vaccination crucially depends on coinjection at the same site of CpG adjuvant and t his response was MHC class II independent. In prime-boost regimes a second mechanism started contributing to CTL induction, namely CD4+ T helper cell mediated CD40L dependent activation of DC. Toll like receptor triggering is therefore very useful in CD8+ CT L priming, while CD40L activation starts operating in boosting.
In addition, quite apart from their activation of CD4+ helper cells, long peptides are superior to exact MHC class I binding pe ptides. It appears that the long peptides generate intracellular reservoirs of antigen for MHC class I & II processing, ensuring consisten t and prolonged cell surface display of MHC-bound peptides. Exact MHC class I binding peptides, in contrast, show only a short half l ife at the cell surface.
The combined data show that a new powerful generation of therapeutic anti-cancer vaccines consists of completely synthetic compounds: specific synthetic peptides and synthetic CpG adjuvants.
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Oral Abstracts
Mannose Receptor Antibody-Mediated Antigen Presentation by Human Dendritic Cells Elicits HLA-Restricted Antigen-Specific Anti-Tumor Immunity Venky Ramakrishna 1, LiZhen He1, John Treml1, John Connolly2, Xi-Tao Wang1, Patricia Smith 1, Laura Vitale 1, Thomas O’Neill1, Charles Jones1, Michael Fanger2, Michael Morse3, Timothy Clay3, Herbert Lyerly3, Michael Endres1, Tibor Keler1.
1 Pre-Clinical Development, Medarex, Inc., Bloomsbury, NJ; 2Immunology and Microbiology, Dartmouth Medical School, Lebanon, NH; 3 Surgery, Pathology and Immunology, Duke University Medical School, Durham, NC.
Targeting recycling endocytic receptors with specific antibodies provides a means for introducing a variety of tumor-associated antigens into human dendritic cells (DCs) culminating in their efficient presentation to T cells. We have generated a human mAb (B11) against the mannose receptor that is rapidly internalized by DCs through receptor-mediated endocytosis. By genetically li nking tumor-associated antigens- pmel17 (gp100) and hCGb to B11, we obtained the fusion proteins, B11-pmel17 and B11-hCGb. Treat-
ment of monocyte-derived DCs from normal donors with these fusion proteins, followed by maturation with CD40L, resulted in the efficient presentation of pmel17 and hCGb to T cells. In both antigen systems, T cells sensitized with DCs bearing antigen prol iferated in response to specific antigen stimulation only and these responses were blocked in the presence of L243 mAb indicating an HLA class II-dependent proliferation. Using synthetic peptides that mimic CD8 and CD4 T cell epitopes derived from pmel17 and hCGb we obtained potent cytotoxic and T helper responses to multiple epitopes. Finally, we show that a cytotoxic T cell response is also
observed on pmel17+ and hCGb+ HLA-matched tumor targets in an HLA class I-restricted fashion as demonstrated by abrogation of target lysis in the presence of W6/32 mAb. These results strongly suggest that, in addition to pmel17, hCGb is a targetable tum orassociated antigen. Altogether our data demonstrate that the specific targeting of soluble exogenous tumor antigen to the DC ma nnose receptor is a feasible approach that can directly contribute to the simultaneous activation of cytotoxic as well as the helper arm of the
immune response via multiple HLA molecules. We are currently extending our investigations to include samples from cancer patien ts with the expectation of initiating clinical studies to test this approach.
8-Color Analysis of Post-Vaccination gp100 209-2M Specific CD8+T Cells in Patients with Melanoma Edwin Walker 1, Daniel Haley1, Walter Urba1. 1Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR.
Post vaccine PBMCs from gp100209-2M melanoma-peptide vaccinated non-metastatic melanoma patients were examined using 8-color (10 parameter) flow cytometry analysis in an effort to delineate subpopulations of gp100 209-2M-specific memory/effector CD8 + T cells.
Cells were stained with the reagent combination of CD8b(PE-Cy7)/gp100 209-2M tetramer(APC)/CCR7(PE)/CD45RA(PE-TxR)/ CD27(PE-Cy5)/CD28(FITC)/CD57(Alexa 700) and a “dump” cocktail of CD19 and CD14 MoAbs conjugated to APC-Cy7. T cells were first pre-selected (gated) for positive expression of CD8b/tetramer/and either ±CCR7 - thus, cells which were CD8b +/tetramer+ and either CCR7+ or CCR7 - were further interrogated for the overlapping expression of CD45RA/CD57/CD28/CD27. Thirty-two
distinct subpopulations of gp100 209-2M tetramer + /CD8+ T cells have been characterized using this staining and multi-parameter flow
cytometry analysis strategy. Discrete selected subpopulations of tetramer +/CD8+ T cells have been sorted based on the concomitant staining profile of CD45RA/CCR7/CD27/CD28 and CD57 MoAbs. These phenotypically discrete subsets of effector and memory CD8+ T cells have been subsequently expanded by 8 day cognate-peptide in vitro stimulation (IVS) in the presence of IL-15 and IL-2, and IVS CD8+ T cells have been further studied for phenotype stability and antigen-specific functional response as measured by
cytokine flow cytometry assessment of IFN-g expression - CFC(IFN-g). Date will be presented on the disparate functional and correlated phenotypic profiles of gp100 209-2M specific effector and memory CD8 + T cell subsets from vaccinated melanoma patients.
This type of multi-parameter assessment of tetramer + CD8+ T cells was performed on PBMCs collected within 2-4 weeks after vaccination, PBMCs collected 12-24 months post vaccination, and PBMCs collected after boosting vaccination, which occurred between 12-24 months after the termination of the initial vaccine regimen. The potential importance of these phenotypically dis tinct effector and memory CD8+ subsets for the maintenance of long-term anti melanoma immunity is discussed.
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Oral Abstracts
Discovery and Characterization of New Antigens for Therapeutic Vaccination Against Breast Cancer Laszlo Radvanyi 1, Devender Singh-Sandhu1, Corey Lovitt1, Scott Gallichan 1, Artur Pedyczak1, Jalil Hakimi 1, Kurt Gish2, Neil Berinstein1. 1Cancer Vaccine Program, Aventis Pasteur, Connaught Campus, Toronto, ON, Canada; 2Genomics Biology, Protein Design Labs Inc., Fremont, CA.
A major hurdle in developing more effective immunization strategies for breast cancer is the need to find new and more powerful tumor-associated antigens (TAA) for generating CTL responses. We report here on the results of a successful antigen discovery program that has identified new genes over-expressed in invasive breast cancer that can potentially serve as new targets for im munotherapy. The three main parts of the program were: 1. New target discovery using microarray-based gene profiling of biopsied tu mor
material in comparison to a large panel of normal tissues, 2. Validation of newly discovered genes at the protein level using i mmunohistochemistry (IHC), and 3. Characterization of class I-restricted CTL responses against the new targets and identification of CTL epitopes. RNA from over 54 fresh tumor biopsies was screened using Affymetrix™ gene chip-based profiling in comparison to RNA isolated from up 150 normal tissues and cells. This analysis allowed us to uncover 5 novel genes specifically overexpressed in breast
cancer which were designated BFA4, BFA5, BCZ4, BFY3, and BCY1. One of these genes, BFA4, was more extensively characterized. Overexpression of BFA4 in invasive ductal carcinoma was confirmed with in situ hybridization (ISH) with DNA probes and IHC analysis with two monoclonal antibodies. BFA4 was also found to be markedly immunoreactive, as determined using a panel of HLAA2.1-binding 9-mer BFA4 peptides that elicited proliferation and IFN-g secretion by human CD8 + T cells after 3 rounds of in vitro
stimulation. The activated T cells generated were also able to kill peptide-loaded target cells and cell lines expressing BFA4. Similar results were obtained with peptides of the other 4 new target genes. The full length BFA4 open-reading frame was isolated from BT474 cells and cloned into pcDNA3.1 and the attenuated poxvirus, NYVAC. Vaccination studies using these expression vectors in HLA-A2.1-Kb transgenic mice demonstrated that a number of key BFA4 peptides functioned as processed and presented epitopes
inducing CD8+ T-cell responses in vivo. Similar results were obtained with DNA plasmid vectors encoding the other four breast cancer TAAs under study. These results indicate that breast cancer cells express a number of hitherto unknown intracellular antigens. BFA4 represents an important member of this new class of intracellular TAAs against which CTL responses can be generated. Vaccines combining BFA4 and other TAAs in multi-antigenic vectors may be a useful immunization approach inducing more potent T-cell responses targeting breast tumors in a wider range of patients than is attainable with antigens currently being used.
Adoptive Immunotherapy
Approaches to Cancer Immunotherapy Based on Breaking Tolerance to Non-mutated Antigens Overexpressed on Metastatic Cancers Steven A. Rosenberg, National Cancer Institute, Bethesda, MD
Multiple cancer-associated antigens recognized by human tumor infiltrating lymphocytes have been identified and characterized. The majority of these antigens are either non-mutated proteins overexpressed on cancers or are antigens expressed only on cancers a nd cells in the germ line. Substitution of anchor residues of the immunodominant peptides from these proteins results in increased peptide immunogenicity and following immunization with these modified peptides, high levels of circulating CD8 + antigen reactive T cells
can be generated in patients with metastatic cancer. Tumor regressions in vivo are sporadic and unpredictable, however, and we have thus explored approaches to increase the anti-tumor potential of these immunologic approaches. In a clinical trial of patients with metastatic melanoma immunized with these melanoma peptides in conjunction with an antibody reactive against CTLA-4, objective cancer regressions were seen in patients associated with autoimmunity including autoimmune colitis and gastritis, autoimmune hepatitis, and autoimmune hypophysitis.
We have conducted a clinical trial in which patients received a non-myeloablative chemotherapy followed by the adoptive transfe r of tumor reactive cells plus high dose IL-2. Forty percent of patients, who were previously refractory to treatment with high dose IL-2 and many with chemotherapy, had objective regressions of metastatic cancer. Lymphocytosis, in vivo persistence and proliferation of the transferred cells and clonal repopulation of the transferred lymphocytes were seen in some patients associated with cancer regr ession and
the occasional onset of autoimmunity to normal melanocytes. These approaches demonstrate that the development of strong reactiv ity against normal melanocyte melanoma antigens overexpressed on melanomas can result in tumor destruction and autoimmunity.
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Oral Abstracts
T Cell Therapies for EBV Associated Malignancies Malcolm Brenner. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX.
Epstein Barr virus is associated with a range of malignant pathologies, each with a characteristic pattern of expression of vir al latency genes. We have been developing T cell therapies to prevent and treat EBV malignancies associated with viral latency Types 3 and 2.
Type 3 Latency: Post Transplant Lymphoproliferative Disease (PTLD) and Immunoblastic Lymphoma: Up to 20% of patients may be afflicted after transplant. While CD20 MAb (Rituximab) may be effective in treating this disease, resistant tumors are observed and the disease may recur. An alternative is to use EBV specific cytotoxic T lymphocyte (CTL) infusions. In more than 300 patients, we have established such lines with >98% success. We have genetically marked the CTL before infusion so that we can track them in vivo. Infusion of as few as 10 7 CTL/m2 is followed by a rapid in vivo expansion of virus specific cells and an equally rapid return of
raised EBV DNA levels to normal. None of 57 patients who received CTL as prophylaxis developed PTLD compared with 12% of controls. CTL also produced complete remissions in patients with bulky PTLD. After solid organ transplantation, expansion in vi vo is more gradual – perhaps because of the continued administration of immunosuppressive drugs, or because of the less “proliferativ e” environment. Nonetheless, a progressive rise in EBV specific CTL can be measured by tetramer analysis, and this is associated w ith progressive control of EBV disease.
Type 2 Latency: Hodgkin Disease and Nasopharyngeal Carcinoma(NPC): EBV-positive Hodgkin tumors develop and grow in patients who have a functional immune response to EBV. This capability is explained by the potent immune evasion strategies displayed by Hodgkin Reed-Sternberg (H-RS) cells. Thirteen patients with EBV-positive HD received gene-marked, EBV-specific CTL. LMP2a peptide tetramer-specific CTL in peripheral blood increased up to 100 fold. In situ marker gene-analysis demonstrated gene-marked CTL
at tumor sites. Of eight patients who received CTL as therapy, six had tumor responses and survived ten to > eighteen months. w ith stable disease. Four of 5 patients who received CTL as adjuvant therapy post SCT are disease free >8mths to >2 yr after infusion. NPC is now being similarly treated. Improving the efficacy of infused CTL: To improve outcomes in HD and NPC, we are: 1) Increasing the frequency of tumor reactive T cells within the CTL. 2) Generating CTL that are genetically modified to be resistant to tumor inhibitory s trategies. 3)
Using lytic CD45 MAb to reduce the numbers of resident T cells and thereby improve the expansion of infused CTL.
FAS Expression Limits the Effector Function of Tumor-Specific T Cells Rebecca Saff1, Elena Spanjaard1, Andreas Hohlbaum2, Ann Marshak-Rothstein1. 1Department of Microbiology, Boston University School of Medicine, Boston, MA; 2Pieris Proteolab AG, Freising-Weihenstephan, Germany.
The pro-apoptotic transmembrane protein Fas ligand (FasL) can serve as a potent effector molecule in tumor immunotherapy. However, its effectiveness is often moderated by self-limiting regulatory mechanisms. Chronically stimulated cytotoxic effector ce lls upregulate both Fas and FasL, and co-expression of these molecules can potentially lead to activation-induced cell death (AICD) and the loss of effector activity. To determine the importance of T cell persistence in tumor immunotherapy, an experimental model was
established using wild-type (DO11/wt), Fas-deficient (DO11/lpr), and FasL-deficient (DO11/gld) Th1 cells from DO11 T cell recep tor transgenic mice as effectors for a model tumor antigen derived from an ovalbumin (OVA) fusion protein. In vitro, Fas-deficient DO11 Th1 cells proliferated more vigorously in response to the OVA+ tumor line than Fas-sufficient DO11 Th1 cells. This increased proliferation translated into increased effector function, demonstrated by increased activity in cytotoxic assays. To test the impact of
AICD in an in vivo tumor model, wild-type BALB/c mice were injected with DO11/wt, DO11/lpr, or DO11/gld Th1 cells and OVA+ tumors. Both DO11/lpr and DO11/gld cells were able to prevent tumor growth and reject established s.c. tumors more effectively than wild-type T cells, demonstrating that Fas expression limits the effector function of conventional tumor-specific T cells both in vitro
and in vivo (Table 1, Table 2). Therefore, resistance to AICD can significantly enhance T cell effector activity.
Table 1. DO11/lpr cells are more effective than DO11/wt cells in preventing A20-tGO tumor growth in vivo.A % of mice that developed tumors
Activation status of DO11 cells Rested Activated
DO11/wt 100 (11/11) 83 (5/6)
DO11/lpr 64 (7/11) 14 (1/7)
A Sublethally-irradiated BALB/cJ mice were injected i.v. with 1x10 6 rested or activated DO11 Th1/wt or Th1/lpr cells. 2x10 6 A20-tGO cells were then injected s.c. and tumor growth was followed. Number of mice is indicated in parentheses.
Table 2. DO11/lpr cells can eliminate established A20tGO tumors more effectively than DO11/wt and DO1 1/gld cells.A % of mice with tumors that regressed DO11/wt 30 (3/10)
DO11/lpr 100 (9/9)
DO11/gld 70 (7/10)
A Sublethally-irradiated BALB/cJ mice were injected s.c. with 2x10 6 A20tGO cells. On day 10 of tumor growth, mice were injected i.v. with 1x10 6 DO11/wt, DO11/lpr, or DO11/gld cells. Number of mice is indicated in parentheses.
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Pediatric Oncology
Allogeneic Hematopoietic Cell Transplants Coupled with Tumor–Reactive Donor Lymphocytes as Cancer Immunotherapy Richard J. O’Reilly, Ekaterina Doubrovina, Guenther Koehne, Michael Doubrovin, Juri G. Gelovani Tjuvajev, Jakob Dupont, Marrow Transplantation Program, Memorial Sloan-Kettering Cancer Center, New York, NY
In recipients of allogeneic marrow transplants, adoptive transfer of limited numbers of donor leukocytes can induce sustained r egressions of multifocal, monoclonal EBV lymphomas, and can also induce durable remissions in over 80 % of patients relapsing with CML, and up to 30 % of those relapsing with AML or myeloma. Results from our clinical trials indicate that infusions providing as few as 103 EBV-specific CTLp can expand to provide sufficient effectors to control widespread EBV lymphomas. Similarly, doses
providing 0.7-1.0 x 10 5 minor alloantigen reactive HTLp can eradicate cytogenetic relapses of CML. While doses of 10 7 HLAmatched CD3+ T cells/kg are associated with a low incidence of severe GVHD if given late post transplant, severe GVHD may be induced with 105-106 CD3+ T cells/kg if administered in the first 6 months post grafting. Furthermore, infusions of HLA-disparate T cells at such doses are associated with a high incidence of severe acute and chronic GVHD at any time post transplant.
As an alternate strategy for adoptive therapy, particularly for acute leukemias which rarely respond to DLI, we have been evalu ating the tumoricidal potential of donor T cells generated against immunogenic peptides of normal oncofetal proteins differentially e xpressed by leukemic cells. Using autologous donor EBV BLCL as APCS loaded with HLA A0201 or HLA A2402-binding peptides of the Wilms tumor protein, WT1, we have been able to generate tetramer + and IFNg+ WT-1 specific T cells from normal HLA A0201+ or
HLA A2402+ adults in concentrations strikingly similar to those generated in response to immunogenic peptides of EBV, such as EBNA-3. These T cells selectively lyse WT1+ primary leukemias and leukemic cell lines bearing the restricting HLA allele, but do not lyse or alter the clonogenic potential of normal HLA A0201 + or A2402+ CD34+ cells from marrow or cord blood. Furthermore, in SCID mice bearing xenografts of human leukemias or carcinomas, differing in their HLA alleles and expression of WT1, serial in vivo
images and subsequent histologic analyses of tumors and normal tissues after adoptive transfer of WT1 peptide-specific HLA A020 1+ restricted T cells transduced to express both HSV-TK and green fluorescence protein, demonstrate progressive and selective upta ke of these T cells in HLA A0201+ WT1+ tumors and specific inhibition of or complete regression of these targeted tumors. Based on these preclinical findings, we are planning clinical trials to assess the activity of donor derived marrow allograft recipients with relapsing or
residual WT1+ acute leukemias.
Adoptive Immunotherapy with Hyper-Expanded Tumor-Reactive T Cells Gregory Plautz1, Li-Xin Wang1, Suyu Shu1. 1Center for Surgery Research, The Cleveland Clinic, Cleveland, OH.
Multi-modality therapy is the framework for most pediatric cancer treatment due to the high level of responsiveness. However, chemotherapy and radiation can induce long-term organ toxicity and second malignancies. Moreover, most of the cumulative dose i s administered to consolidate treatment of minimal residual disease. Thus, tumor-reactive T cells may have utility in pediatric m alignancies following debulking and induction chemo-radiotherapy. In preclinical murine models, we utilized tumor-vaccine draining lym ph
nodes (VDLNs) as the source of antigen-sensitized T cells that were subsequently highly enriched through MACS isolation of the minor L-selectinlo subset. Ex vivo activation with anti-CD3 mAb, and low concentrations of IL-2 (4 U/ml), and IL-7 (10 mg/ml) induced vigorous proliferation of both CD4 + and CD8+ T cells that produced IFN-g specifically in response to the sensitizing tumor. Moreover, adoptive transfer of T cells, alone, to recipients with advanced intracranial, pulmonary, or subcutaneous tumors was
curative without the need for prior lymphodepletion or concomitant IL-2 support. Because the therapeutic effect is proportional to the dose of effector T cells we subjected the VDLN cells to multiple cycles of anti-CD3 activation to determine whether therapeutic efficacy could be preserved during greater than 10 6-fold numerical expansion over a 50 day period in culture. CD8 + T cells predominated the hyper-expanded cultures but, interestingly, multiple TCR Vb families were maintained proportional to their starting f requen-
cies. Adoptive therapy of established pulmonary metastases was effective without lymphodepletion or IL-2 support. Because lymphoid recovery is relatively rapid in pediatric subjects following intensive therapy, we also examined whether a long-term memo ry response arose among lymphocytes that were regenerating during immune-mediated tumor regression. Adoptive transfer of tumorreactive Thy 1.1+ effector T cells into sublethally irradiated congenic Thy 1.2 + hosts with advanced subcutaneous tumors was curative.
Importantly, long-term memory cells arose among both the transferred and regenerating host T cells that were recovered > 140 da ys later, restimulated ex vivo, and transferred to tumor-bearing hosts to mediate tumor regression. In contrast, adoptive transfer into irradiated, non-tumor bearing hosts failed to establish memory in either the Thy 1.1 + or Thy 1.2+ cells. Taken together, these data suggest a potential strategy of in vivo tumor vaccination followed by ex vivo activation of VDLN T cells concurrently with induction
chemotherapy and radiotherapy. Subsequently, T cell adoptive transfer could be used as a minimally toxic form of consolidative therapy to treat minimal residual disease and establish tumor-specific immune memory.
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Oral Abstracts
Immunobiology of NKT and NK Cells in Metastatic Neuroblastoma Robert C. Seeger, Hong-Wei Wu, Shahab Asgharzadeh, Leonid S. Metelitsa. Div. of Hematology-Oncology, Dept. of Pediatrics, Childrens Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, CA.
Preclinical animal models and in vitro studies of human cells suggest that Natural Killer T (NKT) cells have significant anti-t umor capabilities in that they secrete cytokines that have anti-tumor effects (e.g., TNF-a and IFN-g) and that induce Natural Killer (NK) cell cytotoxicity (e.g., IL-2). We hypothesize that 1) NKT and NK cells can traffic to tumors in response to chemokines in the micro environment; and 2) that NKT cells can have an anti-tumor effect both directly by secreting IFN-g and TNF-a and indirectly by activ ating
NK cell cytotoxicity. With microarray expression profiling (Affymetrix U95Av2 arrays), we showed that primary untreated human neuroblastomas produce chemokines. CCL2/MCP-1 and CXCL12/SDF-1 were secreted by 7/8 and 8/8 neuroblastoma cell lines, respectively, and CCL-MCP-1 was required and sufficient to chemoattract NKT cells (transendothelial migration assay). RT-PCR analysis of primary untreated stage 4 neuroblastomas with a Taqmanâ probe/primer set specific for the invariant Va24-Ja18 TCR o f NKT cells and with 3-color immunofluorescence microscopy revealed NKT cells in tumors expressing CCL2/MCP-1. The mean frequency of NKT cells among tumor infiltrating T cells was approximately 41-fold higher than among peripheral blood T cells. Additionally, both NKT and neuroblastoma cell lines secreted chemokines for NK cells. Human NKT cells were not cytotoxic agains t CD1d– neuroblastoma cells unless they were rendered CD1d + by transfection and pulsed with a ligand for the NKT cell TCR (a-
galactosyl ceramide [aGalCer]). Upon hCD1d/aGalCer recognition, NKT cells induced potent cytotoxicity of NK cells, and this depended upon NKT cell production of IL-2 and IFN-g. Of importance, NKT activation of NK cells was not inhibited by the copresence of type 2 cytokines IL-4 and IL-13. Neuroblastoma cells express few or no MHC class I molecules and so may be highly sensitive to NK cell cytotoxicity. Eighteen of twenty-one neuroblastoma cell lines were sensitive to NK cells (<50% viability a fter 6
h) from three donors, and this was independent of tumor cell drug sensitivity, MYCN amplification, and p53 function. Our data support the hypothesis that NKT cells can infiltrate tumors and attract and activate NK cells for cytotoxicity against neurobla stoma cells. These findings likely are relevant for a variety of human malignancies.
IL-12 Induced Regression of Orthotopic Neuroblastoma Tumors: Potential Role for Reversal of Intrinsic Mechanisms of Resistance to Tumor Cell Apoptosis Tahira Khan1, Julie Hixon1, Jim Stauffer 1, Erin Lincoln2, Tim Back2, Jon Wigginton1. 1Pediatric Oncology Branch, NCI-CCR, NIH, Frederick, MD; 2IRSP, SAIC-Frederick, Frederick, MD.
We have shown that systemic administration of IL-12 mediates complete regression of even well-established orthotopic TBJ and Neuro-2a (N-2a) murine neuroblastoma tumors in the majority of treated mice. These observations have provided important preclin ical rationale for a phase I study of IL-12+/-IL-2 in children with neuroblastoma that we are now initiating in the New Approach es for Neuroblastoma Therapy Consortium. Studies to define the mechanisms accounting for these pronounced therapeutic effects have
demonstrated that tumor regression occurs in conjunction with enhancement of local T cell infiltration, inhibition of tumor neovascularization, and marked induction of tumor and/or vascular injury/apoptosis (as assessed by electron microscopy) . Furth er, these histopathologic alterations are accompanied by substantial increases in circulating sFAS-L and IFN-g protein and enhanced expression of the genes encoding caspase-8, TRAIL, FAS-L and Fas within the tumor microenvironment. In vitro, treatment of the murine endothelial cell line EOMA with IFN-g+TNF-a induces increased cell surface Fas expression, reduction in mitochondrial membrane potential (as assessed by TMRM) and sensitization to FAS-mediated (Jo2 or sFAS-L) apoptosis. Although TBJ neuroblastoma cells clearly undergo apoptosis in vivo after IL-12 treatment, they express little or no cell surface FAS either constitut ively, or after in vitro treatment with IFN-g+TNF-a, and are resistant to FAS-mediated apoptosis in vitro. In contrast, N-2a cells do rap idly upregulate Fas after treatment with IFN-g+TNF-a, but remain quite resistant to Fas-mediated killing. Further, although TBJ and N-2a express both TRAIL-R1 and TNF-RI, they are resistant to TRAIL or TNF-a-mediated apoptosis in vitro as well. This resistance to receptor-mediated apoptosis in the neuroblastoma cells can be overcome by treatment with the protein synthesis inhibitor, cyclo heximide. Collectively, these findings suggest that although both endothelial and neuroblastoma tumor cell populations possess the necessary machinery to undergo receptor-mediated apoptosis, an intrinsic inhibitory factor is active and blocks these pathways in
tumor cells in vitro. Thus, the ability of systemically-administered IL-12 to induce apoptosis in death receptor ligand-resista nt tumor cells suggests that divergent pathways may mediate cell death in tumor versus endothelial cell populations in vivo or that admi nistration of IL-12 inhibits or down-regulates an anti-apoptotic factor(s) in vivo that otherwise blocks receptor-mediated apoptosis.
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Oral Abstracts
Imaging
Imaging of Angiogenesis with Dynamic Contrast Enhanced MRI Peter L. Choyke, NIH/CC/DRD, Bethesda, MD
A distinguishing feature of many cancers is their ability to remodel the host microvasculature to recruit new vessels. This cha racteristic has been exploited to improve diagnosis and to target therapy. Angiogenic inhibitors constitute an important new class of a nticancer therapies that will require new strategies for treatment monitoring.
Measuring angiogenesis in vivo remains an important challenge. Although some progress has been made in developing serum markers of angiogenesis such as endothelial precursor cells, most emphasis has been placed on imaging. Conventional contrast enhanced imaging as performed by CT and MRI provides only “snapshots” of the vasculature and is difficult to compare with later time poi nts. Dynamic Contrast Enhanced (DCE)-MRI employs of strategy of repeatedly imaging the entire first ten minutes of contrast kinetics in
order to generate time-signal curves which provide a fuller appreciation of the hemodynamics of the microvasculature.
In order to interpret the complex and unwieldy data sets generated by DCE-MRI (usually 500-1000 images), two compartment pharmacokinetic models are employed. These models presume that the tumor can be divided into a vascular component, into which the contrast agent initially arrives, and an extracellular, extravascular space (EES) surrounding the tumor cells. The contrast agent diffuses from the vascular component at a rate constant, K trans and returns to the vessel from the EES with a time constant k ep. By fitting
the data to a kinetic model, K trans, kep, vees (the fractional volume of the EES) and v v (the fractional vascular volume) can be calculated. These are used to generate parametric images of the tumor. Validation is needed at several levels. The models generally fit the data very well. In vivo validation, however, is quite challenging, as it is difficult to measure physiology deep within a tumor without disturbing it. Finally, there is a growing body of data supporting DCE-MRI’s clinical validation both for diagnosis and treatme nt
monitoring.
Currently DCE-MRI is used for the diagnosis of breast and prostate cancer and for the treatment monitoring for a variety of ang iogenic inhibitors and cytotoxic therapies. More controversial uses of DCE-MRI are its use for drug discovery, early screening an d dosing determinations.
The current generation of low molecular weight contrast agents are not ideally suited because of their tendency to leak from no rmal vessels. Macromolecular contrast agents are currently being tested to improve specificity for angiogenic vessels. New MRI techn iques will also improve the temporal and spatial resolution of DCE-MRI. Finally, more specific contrast agents targeted at specific c ell surface markers likely represent the future of angiogenesis imaging.
Treatment-Induced Anti-Angiogenesis and Apoptosis in Tumors: Imaging of Early Changes Dr. Alexei Bogdanov, Jr., Center for Molecular Imaging Research, Massachusetts General Hospital, Charlestown, MA
Several novel anti-angiogenic therapies induce targeted anti-proliferative effects in endothelial cells by inhibiting signal tr ansduction mediated by the key enzyme, VEGF-receptor tyrosine kinase (KDR). Anti-angiogenic therapy is emerging as an effective strategy t o target and potentially eliminate neoplastic tumor vessels. A KDR inhibitor has been shown to potently inhibit VEGF-R2 phosphory lation and tumor growth in vivo. The main goal of this study was to establish whether MR imaging of tumor blood volume (Vb) could be used as an early predictor of angiogenic response to tumor treatment. Using an absolute blood volume measurement technique a nd a strictly intravascular paramagnetic contrast agent (gadolinium-labeled protected graft copolymer (PGC-Gd), the MR steady stat e measurements of signal intensities in tumor and muscle tissues were comparatively analyzed to assess the anti-angiogenesis indu ced changes in neoplastic vasculature. Athymic mice with implanted human MV522 colon carcinoma xenografts were treated with KDR inhibitor by oral administration (25 mg/kg) and were imaged either after a single day a one-week course of b.i.d. treatments. T he measured Vb was 2.7±0.8% of the total tissue volume for the skeletal muscle and 2.5±1.5% for tumor one week after the implantat ion (n=8). Tumor blood plasma volume selectively and markedly decreased after a single day treatment to approximately 1.3±0.3% of total tissue volume. Absolute Vb was not affected in muscle as a result of treatments. The above Vb measurements were corrobora ted using isotope and correlative histology experiments. Therapy-induced apoptosis in tumor models was also monitored non-invasivel y using optical imaging probe (novel near-infrared fluorescent annexin V derivative). In conclusion, we demonstrated that measure ments of intravascular volume fraction by the steady-state MRI allows the assessment of very early effects of anti-angiogenic drugs, before the tumor volume changes become obvious.
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Oral Abstracts
Radioimmunotargeting
Chaitanya Divgi 1, Maria Batraki1, Neeta Pandit-Taskar1. 1Departments of Radiology and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY.
The premise underlying radioimmunotargeting in cancer is that preferential accumulation in tumor of a radionuclide-conjugated antibody will permit imaging and therapy. Antigen-binding constructs labeled with radioactivity for tumor targeting are being u sed increasingly for imaging and therapy.
Iodine-131 labeled antibodies have been studied most extensively. In addition to its high-energy gamma radiation that permits e xternal detection, 131I emits potentially cytotoxic beta-minus emission. This allows single photon imaging to demonstrate targeting of radioimmunoconjugate to tumor, and quantitation of radioactivity in the body and in serum. The development of iodine-124 has ma de possible the use of iodinated antibodies for PET imaging, thus merging the exquisite sensitivity of PET with the specificity of antigen
targeting.
Iodine is a sub-optimal nuclide for conjugation with antibodies that internalize subsequent to interaction with antigen. In mos t cases, internalization results in dehalogenation of the antigen-antibody complex with release of radioiodine from the cell and a conse quent decrease in cytotoxic potential. Radiometal-antibody conjugates do not suffer from this limitation, and indium-111 has conseque ntly been studied as an imaging agent. Its approximately 3 days half-life and convenient photons make it ideal for imaging, though t ranschelation of metals in vivo results in variably increased hepatic uptake of radioactivity.
As with iodine, positron-emitting radiometals, conjugated with antibodies, are being studied for their utility as PET imaging a gents. While most studies with positron-emitting radiometals are in their infancy, promising data especially in animal models has been generated with copper-64, gallium-68, and yttrium-86.
Genetic engineering has made possible the development of antigen-binding proteins with great potential for radioimmunotargeting . The relatively low absolute uptake of antibodies in tumor has also led to the exploration of novel multi-step targeting systems .
Radiolabeled monoclonal antibodies offer specificity and low toxicity, making them attractive for the detection and therapy of cancer. Murine antibodies have been studied extensively, and have permitted understanding of constraints and opportunities. The next ge neration of radioimmunotargeting will involve tailored non-immunogenic molecules with optimal clearance, conjugated with nuclides w ith suitable characteristics for PET imaging and therapy.
Inhibiting of Inflammatory Mediators
Tumor-Associated Macrophages as a Polarized Type II Phagocyte Population: Role in Progression and Therapy Alberto Mantovani, Istituto di Ricerche Farmacologiche Mario Negri, Milan and Centro IDET, Institute of General Pathology, University of Milan, Milan, Italy
It has long been recognized that leukocytes infiltrate neoplastic tissues (Mantovani et al. 1992). Cells belonging to the monoc ytemacrophages lineage are a major component of the leukocyte infiltrate of neoplasms. Tumor-associated macrophages (TAM) originat e from circulating blood monocytes. Their recruitment and survival in situ is directed by chemokines (Mantovani et al. 1992) and by cytokines which interact with tyrosine kinase receptors. TAM have complex dual functions in their interaction with neoplastic c ells
(the “macrophage balance” hypothesis, Mantovani et al. 1992) but strong evidence suggests that they are part of inflammatory ci rcuits. The available information suggests that TAM are a prototipic, polarized type II mononuclear phagocyte population. We are aware that the view of TAM as a skewed type II macrophage population is problably an oversimplification. Yet, the view of TAM as a polariz ed M2 macrophage is efficacious in summarizing current understanding of the immunobiology of these cells. As polarized type II macrophages, TAM participate in circuits that regulate tumor growth and progression, adaptive immunity, stroma formation and angiogenesis and are a key component of inflammatory circuits which promote tumor progression and metastasis (for review: Balkwill and Mantovani, 2001). Several lines of evidence including genetic analysis and gene targeting support the general hypo thesis of a protumor role of inflammation, and of macrophages in particular (discussed here and in Coussens et al., 2002). The availab le
information suggesting that inflammatory reactions, and polarized infiltrating macrophages in particular, promote tumor progres sion, raises the possibility that the molecules and cells involved may represent novel, valuable therapeutic targets.
Imaging — continued
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Oral Abstracts
Inhibiting Inflammatory Cytokines and Chemokines in the Tumour Microenvironment Frances Balkwill. Translational Oncology Laboratory, Cancer Research UK, London, United Kingdom.
Many epithelial cancers contain a network of inflammatory cytokines and chemokines and some of the processes involved in chroni c inflammation are also active in human epithelial cancers. Endogenous cytokines and chemokines contribute to tumour cell growth and survival and communication between the malignant cells and stromal elements. There is evidence from animal models and human studies that tumour cell production of the inflammatory cytokine TNF-a is a critical factor in this autocrine and paracrine net work.
TNF-a may also initiate and sustain production of other cytokines and chemokines. Chemokines are key determinants of the extent and phenotype of the leukocyte infiltrate in cancers. Specific chemokines influence blood vessel development and some have dire ct effects on tumour cells. The restricted expression of chemokine receptors by tumor cells, may be one important step in the deve lopment of site specific metastasis. Tumor cells from breast, prostate, pancreatic and ovarian carcinomas, neuroblastoma, glioblas toma
and some leukaemias express chemokine receptors. In most instances, the respective ligand is expressed at sites of tumor spread . In ovarian cancer, stimulation of tumour cells with the appropriate chemokine promotes chemotactic migration and cancer cell invas ion; cancer cell growth in low serum conditions and transcription of a restricted range of angiogenic factors, adhesion molecules, p roteases
as well as TNF-a. Agents that antagonise TNF-a or chemokines are currently being assessed in preclinical animal cancer models a nd in phase I clinical cancer trials.
Inhibition of the Growth Promoting Death Signals in Tumor Biology: A Hypothesis Michael Lotze1, Richard DeMarco1, Jukka Vakkila1. 1Surgery and Bioengineering, Molecular Medicine Institute, University of Pittsburgh, Pittsburgh, PA.
Inflammation involves the coordinate interaction of factors including IL1, IL18, and NF kB signalling 1,2 . High mobility group 1
(HMGB1) protein is a critical transcription factor, loosely associated with chromatin which can also be found in the cytosol an d is actively secreted by activated monocytes. Within the cell nucleus it promotes protein assembly. Outside the cell, it binds with high affinity to RAGE (receptor for advanced glycation end products) and potently enhances inflammation. HMGB1 is secreted by activated macrophages, and is released passively by necrotic cells. Hmgb1(-/-) necrotic cells have a greatly reduced ability to pro mote inflammation. Apoptotic cells do not release HMGB1 and bind it firmly to chromatin. Interestingly, cells undergoing apoptosis a re limited in their ability to release this molecule. Activation of myeloid cells results in the redistribution of HMGB1 from the nucleus to the cytoplasm within organelles, presumably endolysosomes. This is characteristic of both IL1 and IL18 as well although their secretion is induced earlier by ATP. Human DCs release IL1 b following specific interaction with alloreactive T lymphocytes following
induction of intracellular calcium increases. 3-4 Specific CD8(+) T cells generate a Ca(++) influx in DCs with enrichment in endolysosomes containing IL1b and cathepsin D at the immunologic synapse with T cells, allowing polarized delivery to the T-cell. Blocking HMGB1 in tumor models is associated with reduction in tumor growth. We propose that the chronic inflammatory environment associated with tumorigenesis leads to a setting in which tumors have dissipated the inflammatory components associated wi th cell death5 including proinflammatory cytokines while promoting the growth enhancing characteristics of HMGB1, enabling tumor progression. We have created eGFP-HMGB1 adenoviral vectors incorporating the expression plasmid derived by Bianchi and will demonstrate its use in evaluation of cytolysis.
Conclusion. Strategies designed to limit the signalling through HMGB1 could be important in cancer therapies.
1. Kolb M et al 2001. Transient expression of IL-1 b induces acute lung injury and chronic repair leading to pulmonary fibrosis. J.Clin.Invest 107:1529-36 2. Li M et al 2001 An essential role of the NF kB/Toll-like receptor pathway in induction of inflammatory and tissue-repair gene expression by necrotic cells. J.Immunol. 166:7128-7135 3. Gardella S et al 1999 IL18 synthesis and secretion by DCs are modulated by interaction with antigen-specific T cells. J.Leukoc.Biol.
66:237-241 4. Gardella SC et al 2002 The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Reports 182-198 5. Scaffidi PT et al 2002 Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191-5
Inhibiting of Inflammatory Mediators — continued
Program printing sponsored by
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Oral Abstracts
Functional Activities Mediated by the IL-10 Related Cytokines: IL-22 and IL-26 Raymond P. Donnelly, Division of Therapeutic Proteins, Center for Biologics Evaluation & Research, FDA, Bethesda, MD
Several, novel, IL-10-related cytokines have recently been discovered. These include two T cell-derived cytokines: IL-22 and IL -26. The ligand-binding chains for IL-22 and IL-26 are distinct from that used by IL-10, however all three cytokines employ a common second chain, IL-10R2 (CRF2-4), to assemble their active receptor complexes. Thus, IL-10R2 is a shared component in at least th ree distinct class II cytokine receptors. The receptor for IL-26 has not previously been defined. Using stably transfected cell lin es that express either wild-type or chimeric class II cytokine receptors, we have determined that the active receptor complex for IL-26 is a heterodimer composed of two receptor proteins: IL-20R1 and IL-10R2. Signaling through the IL-26 receptor complex results in rap id activation of the transcription factors STAT1 and STAT3. Activation by IL-26 can be blocked with neutralizing antibodies agains t IL20R1 or IL-10R2. Other class II cytokines such as IL-10, IL-19, IL-20, IL-22 and IL-24 fail to signal through the combination o f IL20R1 and IL-10R2, demonstrating that this receptor combination is specific for IL-26. IL-10R2 is broadly expressed on a wide va riety of tissues, whereas only a subset of these tissues express IL-20R1. Therefore, the ability to respond to IL-26 is limited by th e expres-
sion of IL-20R1. Recently, we identified several colorectal carcinoma lines that express receptors for IL-22, IL-26 or both. We are now evaluating the effects of IL-22 and IL-26 on the growth and functional activities of these tumor cells in vitro.
The Role of Inflammatory Mediators in Cancer Progression Marian Nakada 1, Xiao-yu Song2, Mohit Trikha1, Li Yan1. 1Oncology Research, Centocor, Malvern, PA; 2 Immunobiology Research, Centocor, Malvern, PA.
The recruitment of leukocytes to tumors has long been believed to be beneficial by providing an anti-tumor immune response that ideally would eradicate the tumor. Indeed, the immune system seems to consider tumors as wounds, acting to promote healing, rather than tumor rejection. In many tumor types, there is an inflammatory response, often stimulated by the tumor cells themselves that can prom ote, rather than prevent tumor growth. In addition, certain inflammatory mediators, such as TNFa, IL-6 and MCP-1, elaborated by the tumor a nd the
host response can accelerate cancer-associated complications including cachexia, fatigue, and bone pain. Inflammatory cells, re cruited by tumor cells and activated stromal cells, secrete pro-inflammatory chemokines and cytokines. These soluble factors then act eith er directly or indirectly through stimulation of the vascular endothelium to recruit leukocytes to the tumor. After activation, these tumor -associated leukocytes, mostly macrophages, release angiogenic factors, mitogens, proteolytic enzymes, and chemotactic factors, recruiting more
inflammatory cells and stimulating tumor proliferation and angiogenesis. New vessels provide greater access for more inflammato ry cells to infiltrate the tumor. Inflammation induces angiogenesis and angiogenesis further stimulates inflammation, leading to tumor g rowth, cachexia and metastasis . Preclinical in vivo data indicate that blocking TNFa will inhibit tumor-induced cachexia; blocking IL6 will inhibit growth of certain tumors and tumor-induced cachexia, and that blocking MCP-1 will inhibit angiogenesis. These data sugg est that
blocking inflammatory mediators may be beneficial in the treatment of cancer.
Anti-MCP-1 Monoclonal Antibodies Effectively Inhibit Tumor Angiogenesis and Growth Li Yan1, Prabakaran Kesavan1, Nicole Stowell1, Francis McCabe1, Don Griswold1, Anuk Das1, Marian Nakada1. 1 Oncology, Centocor, Inc., Malvern, PA.
MCP-1 is a potent chemoattractic factor for monocytes and has been recently indicated to play a pivotal role in tumor angiogene sis, the formation of new blood vessels. Tumor cell-secreted MCP-1 levels have been correlated with blood vessel density in a number of tumors, including breast cancer, squamous cell carcinoma of head and neck and esophagus, gastric carcinoma, and hemangioma. Furthermore, high levels of tumor MCP-1 were found to serve as a prognostic biomarker indicating poor prognosis and early relap se. It has been postulated that MCP-1 in tumor tissues may stimulate angiogenesis by recruiting tumor infiltrating macrophages and stimulating these infiltrating cells to produce angiogenenic growth factors such as vascular endothelial growth factor, tumor n ecrosis factor a, and interleukins 6 and 8. However, the precise mechanisms underlying the role of MCP-1 in tumor angiogenesis have yet to be determined. We have established a simple in vivo angiogenesis model, using human cancer cells expressing different levels of
MCP-1 to study the role of MCP-1 during tumor angiogenesis. Matrigel plugs containing PANC-1 human pancreatic cancer cells, MDA MB 435S or MDA MB 231 human breast cancer cells, were implanted subcutaneously in nude mice. The degree of angiogenic response elicited by these tumor cells in this 8-day study, as determined by hemoglobin levels in the Matrigel plugs (11.81±3.0 6; 7.33±2.71; 4.40±2.05 mg Hb/g Matrigel for PANC-1, MDA MB 435S or MDA MB 231 respectively), correlated well with MCP-1 production levels of these cells (60,185; 5,712; 26 pg/ml/10 6 cells/24hr, respectively). The role of MCP-1 in tumor angiogenesis was
further investigated using anti-MCP-1 monoclonal antibodies (mAbs). Angiogenic response was effectively inhibited to near background levels in animals that were treated with anti-MCP-1 mAbs, administrated intra-peritoneally at 10 mg/kg on days 1 and 5 o f the study. Concomitant inhibition of tumor growth by mAb treatment was also observed in Matrigel plugs containing PANC-1 tumor cells. Our results clearly demonstrated the critical role of tumor cell-derived MCP-1 during tumor angiogenesis and highlighted the potential of anti-MCP-1 mAbs in treating solid tumors.
Inhibiting of Inflammatory Mediators — continued
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Oral Abstracts
Immune Responses to P53 in Patients with Cancer: Elevated Frequencies of Tetramer + P53 PeptideSpecific T Cells and Regulatory CD4+CD25+ Cells at Tumor Sites Compared to the Peripheral Circulation Andreas Albers1, Robert Ferris 1, Theresa Whiteside1, Albert DeLeo1. 1Pathologie, Otolaryngology and Tumorimmunology,
University of Pittsburgh Cancer Institute, Pittsburgh, PA.
Objective: Antitumor immune respnses are dependent on the presence, function and distribution in tissues and blood of T cells specific for tumor-associated epitopes. p53 is “overexpressed” in a majority of human cancers including head and neck cancer (H NC). T cells specific for wild-type sequence (wt) p53 peptides are detectable in peripheral blood of patients with HNC (Hoffmann et al., Cancer Res. 62:1281-1288, 2002). However, it is not known whether T cells specific for wt p53 264-272 and wt p53149-157 epitopes localize
to tumor–involved tissues and whether CD4+CD25+ “regulatory” T cells are present at these sites.
Methods: Using soluble HLA-A2.1+/peptide tetrameric complexes (tetramers) specific for wt p53 264-272 and wt p53149-157 epitopes in four-color flow cytometry, we evaluated samples of tumor infiltrating lymphocytes (TIL), tumor-involved or non-involved lymph n ode lymphocytes (LNL) and peripheral blood mononuclear cells (PBMC) obtained from 9 HLA-A2.1+ patients with HNC. In addition, the frequency of CD4+CD8+ T cells was determined in these samples.
Results: The frequency of CD3+CD8+tetramer+ anti-wt p53264-272 and anti-wt p53149-157 effector cells was elevated in TIL relative to PBMC. In one patient, tumor uninvolved LNL and PBMC had equivalent frequencies of CD3+CD8+tetramer+, while CD3+CD8+tetramer+ T cells accumulated at the tumor site. Thus, anti-wt p53 epitope specific T cells preferentially localize to tumor sites in patients with HNC. At the same time CD4 +CD25+ T cells, considered to play a downregulatory role in anti-tumor immune
responses, were found to be significantly increased (~3fold; p< 0.05) in TILs vs. PBMC.
Conclusions: Our results show that wt p53 peptide-specific T cells are not only present in the circulation but also preferentially localize to tumor sites in patients with HNC. This finding, together with evidence for an increase in regulatory CD4 +CD25+ T cells in TIL relative to PBMC, raises the question about the functionality of the CD8 + T cells accumulation at the tumor site. Our previous results demonstrating dysfunction of T cells obtained from tumors of HNC patients suggest that the tumor microenvironment enric hed
in CD4+CD25+ T cells is not optimal for antitumor effector cells.
L-Arginine Consumption by Macrophages Modulates the Expression of T Cell Receptor CD3Z Chain in T Lymphocytes Paulo C Rodriguez, Arnold H Zea, Jovanny Zabaleta, Juan B Ochoa, Augusto C Ochoa. Stanley S. Scott Cancer Center, Louisiana State University, New Orleans, LA; Department of Surgery, University of Pittsburgh, Pittsburgh, PA.
L-Arginine (L-Arg) plays a central role in the normal function of several organs including the immune system. It is metabolized in macrophages by iNOS to produce nitric oxide, and by arginase I (ASE I) and arginase II (ASE II) to synthesize L-ornithine and u rea; the first being the precursor for the production of polyamines needed for cell proliferation. L-Arg availability can modulate T cell function. T cells cultured under conditions of L-Arg starvation rapidly decrease the expression of the T cell receptor z chain (CD3z), have an impaired proliferation and a decreased cytokine production. The aim of the work presented here was to determine which o f the three metabolic pathways in macrophages that use L-Arg as substrate, could modulate extra-cellular levels of L-Arg and regu late T cell function. The results show that peritoneal macrophages (PM) producing ASE I and expressing the cationic amino acid transpo rter CAT-2B rapidly reduce extra-cellular levels of L-Arg and cause a decreased expression of CD3z chain in stimulated T lymphocytes . Competitive inhibitors of ASE I, CAT-2B or addition of excess L-Arg cause the re-expression of CD3z. In contrast, iNOS and ASE II, or other CAT transporters in macrophages, failed to significantly reduce the extra-cellular levels of L-Arg and modulate the T cell
receptor expression. These results may provide new insights into the mechanisms leading to T cell dysfunction and the down-regu lation of CD3z in cancer and other chronic infectious diseases.
Inhibiting of Inflammatory Mediators — continued
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Presidential Session sponsored by
Reconstitution of Lymphopenic Mice with CD25-Depleted Spleen Cells from Tumor-Bearing Mice, Eliminates Tumor-Induced Suppression, Restores the Tumor-Specific Response to Vaccination and Therapeutic Efficacy of Adoptive Immunotherapy Christian H Poehlein 1, Dan Haley2, Edwin Walker2, Bernard A Fox1,3. 1Laboratory of Molecular and Tumor Immunology,
Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center; 2Laboratory for Immunological Monitoring, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center; 3 Departments of Molecular Microbiology and Immunology, and Biochemistry and Molecular Biology, OHSU, Portland, OR.
We postulate that cancer immunotherapy fails because the magnitude of the anti-tumor immune response is insufficient to mediate tumor regression. We recently reported that vaccination of reconstituted-lymphopenic mice (RLM), undergoing homeostasis-driven proliferation, primed a higher frequency of tumor-specific T cells in the tumor vaccine-draining lymph nodes (TVDLN). The adopt ive transfer of effector T cells (TE) generated from TVDLN of RLM were significantly (p<0.05) more therapeutic than TE generated fr om
“intact” mice. However, these studies reconstituted mice with spleen cells (SC) from naïve mice. Using SC from 8-14 day systemi c tumor-bearing mice (TBM) in the RLM strategy resulted in TVDLN TE cells that had an 80-95% reduction in the frequency of tumorspecific IFN-g secreting CD8+ T cells and no therapeutic efficacy against D5 pulmonary metastases. Here we examined whether depletion of CD25+ cells from SC of TBM used in the RLM strategy would improve the therapeutic effect. Irradiated (500R) C57BL/ 6 mice were reconstituted by i.v. administration of 20 x 10 6 total or CD25-depleted SC from naïve or 8 day TBM and vaccinated with
D5-G6, a mGM-CSF secreting subclone of B16BL6-D5 (D5). TVDLN were harvested, activated with anti-CD3 and expanded in 60IU/ml IL-2 to generate TE. TE generated by reconstitution with naïve total or CD25-depleted SC had similar high frequencies o f tumor-specific IFN-g secreting TE that mediated significant reduction of pulmonary metastases (p<0.05, 2 exps). In contrast, wh ile TBM total SC were ineffective at generating tumor-specific TE in the RLM model, reconstitution with CD25-depleted TBM SC
effectively restored the frequency of tumor-specific IFN-g secreting TE. Coincident with this recovery the TE acquired signific ant therapeutic efficacy (p<0.05, 2 exps), reducing the number of pulmonary metastases by 70-80%. These data document that CD25+ T cells are one mechanism tumors use to escape immune-mediated destruction. Current studies are using eight-color FACS analysis t o characterize the CD25+ and CD25- T cell populations. Since we are initiating clinical trials of the RLM strategy, these finding s may
provide information that can be used to monitor and/or improve the translation of this strategy to the clinic. (Supported by RO1CA80964, the Murdock Trust and the Chiles Foundation. C.H.P. was a Chiles Foundation visiting fellow)
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Oral Abstracts
Vaccination by Genetically Modified Dendritic Cells Expressing the HER-2/neu Oncogene Prevents Development of Spontaneous Breast Cancer in Transgenic Mice Yoshio Sakai1, Brian Morrison1, John Burke1, John Janik1, Masaki Terabe1, Jong-Myun Park1, Guido Forni2, Jay Berzofsky1, John Morris1. 1Metabolism Branch, National Cancer Institute, NIH, Bethesda, MD; 2Clinical and Biological Sciences,
University of Turin, Orbassano, Italy.
Dendritic cells (DC) play a central role in generating immune responses by presentation of peptide epitopes in the context of M HC to interact with T cells. We examined the efficacy of antitumor vaccination using DC modified by a recombinant adenoviral vector ( rAd) expressing the HER-2/neu oncogene in a transgenic mouse model of breast cancer. METHODS: DC were generated from bone marrow of BALB/c mice by culturing in media with GM-CSF. Non-replicating E1, E3-deleted rAds encoding a truncated HER-2/neu cDNA expressing the extracellular and transmembrane domains [Ad.HER2] or no transgene [Ad.null] were generated by standard methods. BALB-neu T mice transgenic for the rat HER2/neu oncogene spontaneously develop breast cancers beginning at 14-15 weeks of age and progress until all 10 mammary gland are involved by tumor. Groups of 5 to 6 week old BALB-neu T mice were injected weekly x 3 with 1x106 DC infected with Ad.HER2 (DC-Ad.HER2), Ad.null (DC-Ad.null), or unmodified DC and then followed for tumor occurrence. Serum and splenocytes were collected from groups of mice prior to treatment and 1-week after the final vaccination. Anti-HER-2/neu antibodies were measured by specific binding potential (SBP). IFN-gamma secretion assays were performed on splenocytes after re-stimulation with DCAd.HER2. Mice free of tumor at 28-weeks were challenged with an injection of 1x10^5 HER-2/neu-expressing TUBO cells. RESULTS: At 28-weeks, 14/21 (66.7%) mice treated with DCAd.HER2 were free of tumor. In contrast, all mice (21/21) in the control groups had developed breast cancers. At 28-weeks, the DCAd.HER2 group had a mean of 2.9 tumors compared to a mean of 10 tumors in the control animals (P<0.05). The efficacy of the DCAd.HER2 was unaffected by pre-existing immunity to adenovirus. In vaccinated mice free of spontaneous tumors, the growth of injected TUBO cells was significantly delayed (53 vs 10 days). DCAd.HER2 vaccination induced greater increases in serum anti-HER-2/neu antibodies as measured by SBP compared to vaccination with DCAd.null or DC alone. The number of CD4+ and CD8+ splenic lymphocytes secreting IFN-gamma in response to DC-Ad.HER2 was increased in the DC-Ad.HER2 vaccinated animals over mice receiving DCAd.null or DC alone. CONCLUSIONS: 1) Vaccination with DC modified by rAd vectors expressing non-signaling HER-2/neu inhibited the development of tumors in a transgenic model of breast cancer. 2) DC-Ad.HER2 vaccination induced production of ser um anti-HER-2/neu antibodies and increased IFN-gamma producing lymphocytes on re-stimulation. 3) The antitumor activity DCAd.HER2 was not affected by pre-exposure to adenovirus.
Adoptive Transfer of CD8+ T Lymphocytes into Lympho-Depleted Recipients Results in Breaking of Tolerance, Autoimmunity, and Cancer Regression Steven Finkelstein1, Paul Antony1, Christopher Klebanoff1, Leroy Hwang1, Paul Spiess 1, Deborah Surman1, Douglas Palmer1, David Heimann1, Zhiya Yu1, Steven Rosenberg1, Nicholas Restifo 1. 1Surgery Branch, NIH / NCI, Bethesda, MD.
Immunotherapies employing adoptive cell transfer can result in the regression of bulky invasive cancer in some patients. Howeve r, currently available therapies are less successful than desired. A novel murine model system with analogous components to the treatment of human patients was established to study the mechanism of action and to study possible improvements in cell transfe r therapies. Lympho-depletion was accomplished either by sub-lethal irradiation of C57BL/6 mice or through the use of mutant or genetically engineered mouse strains devoid of lymphocytes including nude mice, SCID mice, or Rag-1 knockout mice. Adoptive cel l transfer was undertaken alone or in combination with IL-2 cytokine administration and/or a fowlpox virus encoding the melanocyt e differentiation antigen, human gp100 (hgp100-FP). Tumor regression was observed in all mice after receiving lympho-depletion followed by adoptive transfer of Pmel-1 + hgp100-FP + IL2. When optimal treatment was employed, this approach led to the comple te regression of large (>1cm in diameter) tumor burden. This regimen prolonged the survival of mice when compared to no treatment, Pmel-1 cells only, Pmel-1 cells + IL-2, or Pmel-1 + hgp100-FP without IL-2. FACS analyses of peripheral blood and splenocytes from successfully treated mice revealed persistence of transferred Pmel-1 cells. Complete responders developed autoimmunity wit h vitiligo noted at the former tumor site that spread to involve the whole coat. These data suggest that adoptive transfer of sel f-antigen specific CD8+ T cells into lympho-depleted recipients can lead to the breaking of tolerance, autoimmunity, and cancer regressio n. These findings have important implications for the design of immunotherapy trials in humans.
Presidential Session — continued
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Oral Abstracts
Coordinate Expression of Chemokine Receptor 6 (CCR6) and CCR7 in Squamous Cell Carcinoma of the Head and Neck (SCCHN) – Identification of a Metastatic Phenotype Jun Wang1,2, Liqiang Li1,2, Jennifer Hunt 1, Theresa Whiteside1, Tony Godfrey1, Robert Ferris1,2. 1Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA; 2Otolaryngology and Immunology, University of Pittsburgh, Pittsburgh, PA.
Objectives: Whether tumor metastasis is an active or passive process is controversial. Tumor cells have been shown to express various receptors that enable their access to the lymphatic system and facilitate metastatic spread to lymph nodes (LN) or other organs . SCCHN usually spreads locoregionally to cervical LN with low frequency of systemic metastasis. We hypothesized that SCCHN cell migration and metastasis may share similarities with leukocyte trafficking, which is regulated by chemokines and their receptor s.
Methods: Expression of chemokine receptors (CCRs) in SCCHN cell lines and snap-frozen tumor tissues by quantitative RT-PCR was performed, using paired cell lines from primary and metastatic tumors and fresh, paired primary and metastatic specimens. F low cytometry for CCRs on cell lines and immunohistochemistry of patients’ primary and metastatic tumors confirmed the presence of surface protein in these cells, as opposed to surrounding lymphoid tissue. Chemotaxis assays and CCR specific antibody blocking
experiments confirmed the functional nature and CCR specific effects observed.
Results: Comparing CCR expression between the primary tumor and its metastatic subpopulations using qRT-PCR and functional migration assays, a consistent pattern arose of CCR6 downregulation and upregulation of CCR7 in metastatic cell lines and tissu es. Chemotaxis assays and CCR specific antibody blocking confirmed the qRT-PCR results, showing that functional surface receptors a re indeed present. CCR6 was nearly universally downregulated, consistent with the emigration of metastatic cells from peripheral mucosal sites, while CCR7, important for homing of immune cells to secondary lymphoid organs, was consistently upregulated in these metastases.
Conclusions: These results indicate a novel metastatic phenotype in SCCHN, exploiting a mechanism used by human dendritic cells (DC), during the normal maturation and trafficking to LN. Our findings indicate CCR6, CCR7 and their ligands may have an import ant role in determining SCCHN metastasis, and may help explain the consistent metastatic propensity for cervical nodal metastasis o bserved in this disease. Wer show than inhibiting CCR7 signalling may represent a targeted anti-metastatic therapeutic approach for SCC HN.
Cytokines-Polymorphisms
The Tumor Necrosis Factor and Interleukin-10 Loci in Colorectal and Breast Cancer Grant Gallagher, Joyce Eskdale, University of Medicine and Dentristryof New Jersey, Newark, NJ
The human TNF and IL-10 loci are recognized as being of fundamental importance in the control of infectious disease outcome. However, their role in the presence and severity of malignant disease is less well defined. Both these loci are highly polymorp hic and markers have been associated with differential cytokine production. For example, the TNFa2 micro satellite allele is associated with higher TNF production and the IL10.R3 allele with lower IL-10 production. We examined the distribution of TNF and IL-10 alleles in
colorectal cancer patients and breast cancer patients. In colorectal cancer, the TNF a2 (high secretion) was strongly associate d with the presence of tumor, as part of the a2b3c2d4 haplotype. No association was seen in breast cancer. While TNF aleles were not assoc iated with the presence of liver metastases, alleles at the TNF-R1 locus showed association with metastatic presence. Neither TNF nor IL10 alleles were associated with breast cancer per se, but the IL10.G14 (high secretor) allele was associated with lymph-node ne gative tumors, suggesting that high IL-10 was protective from metastatic spread. Interestingly, a comparison of tumor and normal tissu e from breast cancer patients showed clear evidence of loss of heterozygosity at the IL-10 locus in this tumor, suggesting that, in so me
patients, IL-10 may function a tumor suppressor gene for breast cancer.
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Type I TGF-beta Receptor Polymorphisms and Breast Cancer Risk: New Data and a Meta-Analysis Elad Ziv*, Elaine Carlson, Jon Wong, Esther M. John, *contact author: Elad Ziv, MD, UCSF Women’s Health Research Center, San Francisco, CA
Background: Transforming growth factor - beta1 (TGF-b1) activity may be associated with breast cancer risk. A polymorphism in the Type I TGF-beta receptor (TGFBR1) leading to conversion of a 9 alanine (9A) to a 6 alanine (6A) repeat in exon 1 of the gene ha s previously been associated with cancer risk in some studies. Therefore, we tested the association with the 6A allele and breast cancer susceptibility
Methods: We tested the association between the 6A allele and breast cancer in a population-based case-control study of women i n the San Francisco Bay Area. Women with breast cancer were sampled from 3 ethnic groups, African Americans (n=214), Caucasians (n=231) and Latinos (n=241) using the Bay Area Cancer Registry. Age and ethnically-matched controls were selected by random dig it dialing (Whites, n=248; African Americans, n=232; Latinas, n=334). We also performed a meta-analysis of TGFBR1 polymorphisms and breast cancer risk. All studies which reported odds ratios for breast cancer, or for which odds ratios for breast cancer co uld be
calculated were included. We used a random effects model to calculate the summary odds ratio.
Results: There were significant differences in allele frequencies among the 3 ethnic groups with whites having the highest fre quency of the 6A allele, followed by Latinas and African Amerincans. In our study there was a non-significant trend towards an increas ed risk for breast cancer among 6A carriers (OR: 1.27; 95% CI: 0.94 - 1.71; p=0.1). The estimates for association were consistent among all ethnic groups included in the study. We identified 2 other published studies of TGFBR1 which met our inclusion criteria. Combin ing these studies with the current study, we identified a significantly increased risk of breast cancer among 6A allele carriers (S ummary
OR 1.42; 95% CI: 1.15-1.74; p=0.0005). We found no evidence for heterogeneity among the studies included (p=0.95).
Conclusions: The 6A allele of TGFBR1 is associated with a modestly increased risk of breast cancer. However since this allele is relatively common it may be associated with a substantial fraction of breast cancers. Studies of other genes in this pathway ma y help to further refine individual risk profiles for women.
Interleukin-10 and Other Cytokine Polymorphism in Melanoma and Prostate Cancer Stephen Chanock, National Cancer Institute, Gaithersburg, MD
Cytokine Gene Polymorphisms and Angiogenesis in Cutaneous Malignant Melanoma and Prostate Cancer W Martin Howell and collaborators1. Molecular Pathology Laboratory, Southampton University Hospitals and Division of Human Genetics, University of Southampton, Southampton, UK
Cytokines play a crucial role in regulating immune responses. Studies in many laboratories have identified a range of single nu cleotide (SNP) and microsatellite polymorphisms in pro- and anti-inflammatory cytokine genes and related growth factors that appear to b e associated with differential in vitro cytokine production. These polymorphisms may play a role in determining inter-individual differences in immune responsiveness and anti-tumor immune responses in those malignancies in which such responses occur. In addition, part icular
cytokines (e.g. IL-8, IL-10 and VEGF) may also influence tumor development via their action on pathways of angiogenesis.
We have sought to determine associations between SNPs in pro- and anti-inflammatory cytokine and growth factor genes and suscep tibility to and markers of prognosis in two principal malignancies - cutaneous malignant melanoma (CMM) and prostate cancer (PC ). In CMM, we have examined 20 SNPs in the TNFA, LTA, IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IFNG, TGFB and VEGF genes, in a series of 165 CMM cases and 266 cancer-free controls (all Caucasians). Results indicate that SNPs and haplotypes associated wit h
low IL-10 expression were significantly increased in frequency in patients versus controls, while genotypes associated with hig h VEGF expression were elevated in frequency among the patient group. In addition, genotypes and haplotypes associated with eleva ted IL-10 expression were associated with non-invasive tumour growth phase, while genotypes and haplotypes associated with lower IL 10 expression were associated with a more advanced stage of disease and thicker invasive tumours. Genotypes associated with low er VEGF expression were associated with thinner invasive primary tumours. These results suggest that IL-10 polymorphism may influence both susceptibility to and markers of prognosis in CMM, with high expression genotypes conferring protection from and low expression genotypes acting as a risk factor for tumor development - consistent with anti-angiogenic properties of IL-10. VEGF
results are consistent with the strongly angiogenic properties of VEGF.
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Results from an initial study of 247 Caucasian PC patients and the same control group are broadly similar, with genotypes assoc iated with lower IL-10 production showing a significant association with disease, while genotypes associated with lower IL-8 and VEGF expression were significantly decreased among the patient group. IL-8 ‘high producer’ genotypes were also significantly associa ted with prostate specific antigen level at diagnosis. These results suggest that SNPs associated with differential production of I L-8, IL-10
and VEGF are risk factors for PC, possibly acting via their influence on pathways of angiogenesis.
Studies are currently underway to confirm and extend the above findings in these and other malignancies.
1 AC Bateman, JM Theaker, RA Eeles, D Dearnaley, DF Easton, The Cancer Research UK/British Prostate Group United Kingdom Familial Prostate Cancer Study Collaborators.
Angiogenesis Monitoring Follow-up
Endogenous Inhibitors of Angiogenesis are Tumor Suppressors Raghu Kalluri, Beth Israel Deaconess Medical Center, Boston, MA
Progression of cancer is dependent on angiogenesis. Relative levels of pro- and anti- angiogenic factors, the ‘angiogenic balan ce’, likely govern tumor progression. While the role of pro-angiogenic factors such as VEGF and FGF is well established, emerging evidence suggests that anti-angiogenic factors such as thrombospondin-1, tumstatin, endostatin and canstatin are important for maintenance of the angiogenic balance. Conversion of dormant in situ carcinoma into an invasive malignant phenotype is consider ed
to involve a shift in favor of enhanced ‘angiogenesis potential.’ Influenced by oncogenes and tumor suppressor genes, disruptio n of the ‘angiogenic check point’ via increase in angiogenic factors such as VEGF or decrease in the physiological levels of endogenous inhibitors of angiogenesis like thrombospondin-1 and tumstatin could represent an important lethal step in the progression of c ancer. Recent evidence suggests that vascular integrins are critical mediators of the action of endogenous inhibitors of angiogenesis. Thus,
genetic control of the physiological levels of endogenous inhibitors of angiogenesis and their vascular integrin targets might constitute a critical last line of defense against conversion of neoplastic events into a malignant phenotype of cancer.
Molecular Diversity and Targeted Therapy Renata Pasqualini, Wadih Arap, MD Anderson Cancer Center, Houston, TX
Despite major progress brought about by the Human Genome Project, the molecular diversity of human blood vessels remains largel y unexplored. Our research is aimed at targeting diagnostic and therapeutic agents to blood vessels by using probes that can bind to specific vascular addresses.
Towards this goal, we developed technologies to identify small peptides that target the endothelium. Different strategies are u sed to isolate peptides from large libraries displayed in the surface of bacteriophage. Through this platform technology, we have unco vered various tissue-specific and angiogenesis-related vascular addresses. This complex system of ligand-receptor pairs will lead to a better understanding of tumor circulatory microenvironment, changes in blood vessels during tumor progression, and the localization of
novel markers in cancer and other diseases with an angiogenesis component.
This lecture will review several targeting strategies that may enable the construction of a molecular map outlining vascular di versity in each organ, tissue, or disease.
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Homing of Dendritic Cells to Lymph Nodes Depends on Self-Produced Angiogenic Factors Christine Odoux 1, Andreas Albers1, Simon Watkins1, Michael Wong2, Theresa Whiteside1. 1Pathology-Otolaryngology, University of Pittsburgh; 2Molecular Pharmacology, Roswell Park Cancer Institute, Buffalo, NY.
Objectives: Homing of dendritic cells (DC) to lymph nodes, a critical step of the host immune response, is dependent on DC maturation and their interactions with endothelial cells (EC). We previously showed, using an in vivo matrigel assay in the mouse model, that bone marrow-derived DC injected subcutaneously into recipient mice induced vascular neo-genesis. DC localized close to new vessels, and immature DC (iDC) induced more angiogenesis than mature DC (mDC), as shown by Factor VIII immunostaining and hemoglobin measurement. To further clarify the involvement of DC in angiogenesis, factors regulating DC-induced angiogenesis an d
DC homing properties were investigated.
Methods: Following the in vivo matrigel assay, migrating cells were studied by immunofluorescent staining for CCR7, a receptor necessary for cell homing to lymph nodes, and various DC maturation marker expression on matrigel cryosections. Newly formed vessels were examined by immunostaining for factor VIII and by measuring hemoglobin contained in matrigels. In vitro, angiogenic factor and cytokine production was measured in culture supernatants of mDC and iDC using immunoassays. Chemotactic assays were
performed to measure the ability of DC to migrate in response to a chemotactic cytokine for mDC, CCL19.
Results: Our results show that murine bone-marrow derived-DC (iDC and mDC) secrete angiogenic factors, including bFGF and VEGF, and that LPS stimulation increases production of these factors. In vivo, interaction of iDC with EC initiates angiogenesis, which can be blocked by injection of a neutralizing anti-basic FGF antibody. Thus, DC-induced angiogenesis is dependent on the ability of DC to secrete bFGF. As they mature, DC localize in close proximity to blood vessels and acquire CCR7. In in vitro chemot-
actic assays, we demonstrate that DC migration is dependent on expression of CCR7 on mDC. These cells migrated in response to CCL19, a chemokine signaling via CCR7. Migration of CCR7+DC was significantly greater than that of iDC. Furthermore, addition of PGE2, a known angiogenic and DC maturation factor, to CCL19 significantly increased DC migration in vitro. Similar experiments performed in the human system, using monocyte blood derived-DC cultured in presence of IL-4 and GM-CSF showed similar ability
to secrete angiogenic factors and increased migration in response to CCL19 of mDC stimulated with PGE 2. Conclusion: Murine activated iDC in tissue sites acquire angiogenic activities. The angiogenic vessels produced in situ allow mDC migration to lymph nodes. Further, human blood-derived in vitro DC gain similar angiogenic functions. Regulation of DC angiogenic activity and thus their migration represents a novel strategy for the enhancement of immune reactivity in future clinical inves tigations.
Anti-VEGF Therapy by Hydrodynamic Delivery Suppresses Growth of Renal Cell Carcinoma That Expresses Multiple Pro-Angiogenic Factors Hiroshi Yazawa1, Takaya Murakami2, Timothy Back3, Yasuhiro Suzuki1, Erin Parsoneault 3, Martha Gruys1, Robert Wiltrout1, Morihiro Watanabe 1. 1LEI, NCI-CCR, Frederick, MD; 2LMI, NCI-CCR, Frederick, MD; 3NCI at Frederick, Frederick, MD.
Most renal cell carcinomas (RCC) are hypervascular tumors that produce pro- and anti-angiogenic factors. In particular, overexpression of vascular endothelial growth factor (VEGF) is related to poor prognosis for RCC patients and strategies that t arget the VEGF ligand or its receptors may have therapeutic value. This study uses the Renca mouse RCC model that expresses a complex profile of angiogenesis-related factors to understand the importance of VEGF relative to other tumor-associated pro-angiogenic factors. DNA arrays revealed expression of pro- and anti-angiogenic genes including VEGF-A and HIF-1a that are also associated with human RCC, as well as VEGF-B and -D, osteopontin, pleiotropin, midkine, angiogenin, hepatocyte growth factor, angiopoietin 2, TIMP-1 and -2. Expression vectors encoding the soluble forms of the VEGF receptors (VEGFR), Flk-1 and Flt-1, linked to the constant region of human IgG1 were generated and designated, pFlk-hFc and pFlt-hFc, respectively. Supernatants from transient transfections with these plasmids inhibited VEGF-driven human umbilical endothelial cell (HUVEC) proliferation and chemotaxis. HUVEC chemotaxis induced by VEGF-containing conditioned medium from cultured Renca cells was also substantially inhibited by these supernatants. In vivo gene expression of Flt1-hFc, Flk1-hFc or the combination, after hydrodynamic injection, successfull y inhibited angiogenesis in VEGF-containing matrigel by 57 %, 47 % and 53 % and subcutaneous Renca growth, by 85%, 69% and 54% respectively, compared with a control vector treated group. The results show that even though the Renca tumor expresses multiple angiogenic factors, therapy focused on only VEGF can be an effective antitumor strategy, if the blocking is highly eff icient.
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Analysis of Angiogenic Factors in Cultured Cell Supernatants, Sera, and Plasma Using a Multiplexed 9-Analyte Angiogenic Array Scott Orencole1, Scott Van Arsdell 1, Christine Burns 1. 1Research and Development, Pierce Boston Technology Center, Woburn, MA.
An array to detect nine factors (TIMP-1, ANG-2, PDGF-BB, Tpo, KGF(FGF-7), HGF, FGF-basic, VEGF, and HB-EGF) associated with angiogenesis is reported. Printing 20 nl spots of 9 separate capture antibodies in a microplate well enables multiplexing. The chemiluminescent substrate, converted by the streptavidin-horseradish peroxidase-biotinylated detection antibody complex at eac h of the printed spots of antibody, is imaged with a CCD camera. The CCD image is analyzed with software to define and measure the
light density at each spot. Matched sera and EDTA plasmas from healthy donors were assayed using the angiogenic array. All nine analytes were detected in sera and plasma, with the majority measuring levels of approximately 1000 pg/ml. Purified human perip heral blood mononuclear cells cultured with a variety of factors were assayed in the same angiogenic array. Immunostimulatory fa ctors, such as TNF-alpha and IFN-gamma, increased production of TIMP-1, HGF, KGF, VEGF and Tpo. Immunosuppressive cytokines, such as IL-4 and IL-10, increased the levels of PDGF-BB and HB-EGF while showing minimal or no increase in production of other factors. The SearchLight (TM) angiogenic array can aid in understanding the role of multiple growth factors in the regulation o f
angiogenesis.
Genomics
Transcriptional profiles of dendritic cells in response to inflammatory stimuli P. Ricciardi-Castagnoli and F. Granucci, University of Milano-Bicocca, Milan, Italy
Dendritic cells (DCs) sustain the inflammatory process and participate to the innate response. Nevertheless, they are also able to prime adaptive immunity. The strategy of DCs to accomplish these biological effects resides in their ability to segregate in time dif ferent functions starting from the perturbation arrival. Thus, after recognition of an infectious agent, resting, immature, highly pha gocytic DCs, residing in non-lymphoid tissues, undergo a maturation process that leads to precise cytoskeleton modifications required f or
phagocytic activity, down-regulation and acquisition of the migratory capacity. Maturing DCs migrate from non-lymphoid tissues to draining lymph nodes to prime T cell responses. Moreover, during the maturation process DCs express, with a strictly defined ki netic, cytokines and cell surface molecules critical for activation and control of innate and adaptive immune responses.
Global gene expression analysis has found large application in the field of immunology, as it has clearly emerged that the stud y of a single immunological parameter at a time it is not sufficient to reach a general vision of how the immune system faces a partic ular pathogen, maintains self tolerance or remembers past infections. An interesting feature of DC is that they respond to perturbat ions (invading pathogens) without destroying self-tissues. To exert this function DC uses at least three different approaches. They respond,
in a few hours, to infectious agents (innate immunity) by recognizing molecular patterns typical of microorganisms and absent i n selftissues; they mount a late response that discriminates among different microbes giving rise to memory (adaptive immunity), and, finally, they maintain tolerance against self-proteins.
The development of culture systems that allow to maintain and expand immature human and mouse DCs and to mimic in vitro the process of DC maturation has given the possibility to obtain large quantity of immature and maturing DCs at distinct stages of activation upon encounter with different stimuli. Microarray technology has been extensively applied to human and mouse DCs and unpredictable and important information concerning how DCs interact with pathogens and prime immune responses have been obtained.
The most unanticipated finding of global gene expression analysis on maturing mouse DCs was that they produce IL-2 transiently at early time points following activation with bacteria, but also parasites and helminth. IL-2 production by DC is also induced by bacteria cell products, such has LPS, lipoteichoic acid (LTA) and CpG, but not by inflammatory cytokines. The importance of DCderived IL-2 in priming T cell responses has been highlighted by the fact that bacterial activated IL-2-/- DCs are severely imp aired in their capacity to stimulate both CD4 and CD8 T cell responses when compared to wild type DCs. The kinetic of IL-2 production by activated DCs is compatible with the appearance at the cell surface of peptide-MHC class I and class II complexes. Exogenous so urces of IL-2 for T cell activation may be required when the frequency of antigen-specific T cells or the affinity for peptide-MHC co mplexes is very low as it could frequently happen in vivo during immune reactions to invading pathogens. Interestingly, among APCs only DCs and not macrophages are able to produce IL-2 following bacterial encounter.
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Finally, using a global transcriptional approach, an inducible type I IFN-dependent pathway leading to an inflammatory signatur e was found in myeloid DC treated with Schistosoma eggs showing that specific DC immune functions are acquired depending on the type of signal, DC encouter.
Granucci F, Zanoni I. Feau S, Ricciardi-Castagnoli. Dendritic cell regulation of immune responses: a new role for interleukin 2 at the intersection of innate and adaptive immunity. EMBO J. 2003 Jun 2;22(11):2546-51. Granucci F, Feau S, Angeli V, Trottein F, Ricciardi-Castagnoli P. Early IL-2 production by mouse dendritic cells is the resul t of microbial-induced priming. J Immunol. 2003 May 15;170(10):5075-81
Granucci F, Ricciardi-Castagnoli P. Interactions of bacterial pathogens with dendritic cells during invasion of mucosal surface s. Curr Opin Microbiol. 2003 Feb;6(1):72-6. Review. Ricciardi-Castagnoli P, Granucci F. Interpretation of the complexity of innate immune responses by functional genomics. Nat Rev Immunol. 2002 Nov;2(11):881-9.
Granucci, F., C.Vizzardelli, N. Pavelka, S. Feau, M. Persico, E. Virzi, G. Moro, M. Rescigno and P. Ricciardi-Castagnoli (2001) . Inducible IL2 production by dendritic cells revealed by global gene expression analysis. Nature Immunology 2:882-888. Granucci, F., C.Vizzardelli, E. Virzi, M. Rescigno and P. Ricciardi-Castagnoli (2001). Transcriptional reprogramming of dendritic cells by differentiation stimuli. Eur. J. Immunol. 31:2539-2546.
Andrews DM, Andoniou CE, Granucci F, Ricciardi-Castagnoli P, Degli-Esposti MA.(2001) Infection of dendritic cells by murine cytomegalovirus induces functional paralysis. Nature Immunology 2(11):1077-84.
Analysis of expression profiles based on mechanistic expectations. R. Hashimoto1, Y. Jiang2, S. Kim4, E. Dougherty3, G. Hostetter 4, E. Suh, J. Trent 4, M. Bittner41Computer Sciences, Universidade de São Paulo; 2Cancer Genetics Branch, NIH; 3Electrical Engineering, Texas A&M; 4Translational Genomics Research Institute
It has been demonstrated that expression profiling, measurements can lead to the accurate recognition of known tumor types as w ell as to the discovery of particular subtypes of cancers distinguishable on the basis of their gene expression patterns, but not by c lassical histopathologic methods. Approaches to finding these classes fall into two general types. Methods based on mathematical tools f or viewing data in ways that show general trends, such as graphs based on cluster analysis or multi-dimensional scaling are utiliz ed. Alternatively, distributional analysis methods that use some form of discriminant analysis to find genes whose expression patte rn
differentiates between the classes can be employed. Such tests provide associations, but do not utilize even very simple expect ations that arise from the mechanisms operating to produce gene regulation. Model-based testing allows one to use further filtration t o classify gene behavior at a finer level than consistent behavior, enabling the detection of processes operating in what looks t o be a relatively homogeneous molecular pathological subtype. A method has been implemented that looks for blocks of genes that behave in
a way expected, if they are sometimes subject to primary control due to the action of a single gene, but subject to control by a variety of other genes when the acute control provided by the single gene is not activated. Analysis with a focus based on mechanistic expectations provides a way to directly identify genes with strong control activity, a considerable improvement over simply hav ing sets of genes showing coordinated regulation. An example of the use of this method to identify a gene with significant regulato ry
capabilities in melanoma will be provided.
Quiescent Phenotype of Tumor-Specific CD8+ T Cells Following Immunization Vladia Monsurro 1, Ena Wang1, Yoshisha Yamano2, Stephen Migueles3, Monica Panelli1, Kina Smith1, Dirk Nagorsen1, Mark Connors3, Steven Jacobson2, Francesco Marincola1. 1Immunogenetic Section of the Department of Transfusion Medicine, CC/NIH, Bethesda, MD; 2Viral Immunology Section, Neuroimmunology Branch, NINDS/NIH, Bethesda, MD; 3The Laboratory of Immunoregulation,
NIAID/NIH, Betehsda, MD.
In a human melanoma model of tumor-antigen (TA)-specific immunization, we tested directly ex vivo the cytotoxic and the proliferative potential of TA-specific CD8+ T cells. A “quiescent” functional status of activation was identified. This status was furth er characterized combining magnetic sorting using vaccine specific tetramers, RNA amplification and microarray technology. We compared in this way the genetic signature of the “quiescent” phenotype to their progeny deriving from a cycle of in vitro sensitization (IVS). “Quiescent” circulating tumor-specific CD8+ T cells were deficient in expression of genes associated with T cell activat ion, proliferation and effector function, such as perforin, granzyme-A, -B, NK4 and NKG5. Additional genetic markers were identified that provide a global view of this “quiescent” phenotype. This “quiescent” phenotype may explain the lack of correlation betwee n the expansion of circulating immunization-induced lymphocytes and tumor regression. In addition, the prompt activation following in vitro antigen recall and expansion with interleukin-2 suggests that a complete effector phenotype might be re-instated in vivo to fulfill
the potential of anti-cancer vaccine protocols.
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Endothelium Growth Factor-Activation Protein, a Novel Target for Cancer Treatment Validated by SiRNA Mediated Gene Knockdown In Vivo Jun Xu1, Qing Zhang2, Yijia Liu 1, Qingquan Tang1, Martin Woodle1, Patrick Lu1, Lu-Yuan Li2, Frank Xie1. 1Genomics and Drug Development, Intradigm Corporation, Rockville, MD; 2Cancer Institute, University of Pittsburgh, Pittsburgh, PA.
Endothelium growth factor (EGF) signal pathway plays an important role in cell proliferation and tumorigenesis. Recently emerge d RNA interference (RNAi) has been broadly applied in gene function discovery and target validation through silencing of specific ally targeted gene. Using Efficacy-First discovery method, we have found that a novel membrane-bound protein named as Endothelium Growth Factor-Activation Protein (EGF-AP) was significantly upregulated in growth-accelerated MDA-MB-435 xenograft tumor, and
it was also correlated with a group of well-known tumorigenic genes. We then used a method called Disease-Control to further validate the biological function of EGF-AP using siRNA-mediated gene knockdown in the same xenograft tumor model. When the siRNA duplexes specifically targeting EGF-AP were delivered intratumorally, the tumor growth was significantly inhibited due to silencing of EGF-AP gene. To reveal its cellular function, we first transfected EGF-AP specific siRNA into MDA-MB-435 cell and observed a remarkable increase of the apoptosis activity. We then treated the head and neck squamous cancer cell with EGF-AP specific siRNA, and found that the EGF activated MAP kinase pathway was shut down. Together, those data strongly suggest that EGF-AP plays an important role in the growth factor activated tumorigenesis pathways and it would be a novel target for cancer treatment. Because EGF-AP is a membrane protein, and may act as a protease, we anticipated that the EGF-AP should be a perfect target for drug development with monoclonal antibody, small molecules and more recent modality of siRNA agent.
New Agents in Development Session sponsored by
Phase I Dose Escalation Study to Assess the Safety and Pharmacokinetics of Recombinant Human IL18 (rhIL-18/SB485232) Administered as Five Daily Intravenous Infusions in Adult Patients with Solid Tumors M.J. Robertson, J. Mier, M. Atkins, T. Logan, J. Weisenbach, S. Roberts, C. Oei, K.M. Koch, S. Kathman, T. McIntosh,
W. Bell, M. Dar, L. Pandite
In an ongoing phase I dose-escalation study, rhIL-18 (SB485232) is administered as a 2 hour infusion daily for 5 consecutive da ys to patients (pts) with solid tumors. Seven dose levels (3, 10, 30, 100, 300, 600, 1000 ¼g/kg/day) are planned. The study’s objecti ves are to determine safety and tolerability, to define a biologically effective dose, and to assess pharmacokinetics, antigenicity, immunomodulatory and anti-tumor activity of rhIL-18. Only pts with undetectable serum IL-18 antibodies at screening are eligibl e. Twenty pts have been treated: 3 at 3, 4 at 10, 3 at 30, 6 at 100, 3 at 200, and 1 at 300 ¼g/kg/day. Seventeen pts had metastati c renal cell carcinoma that failed prior cytokine therapy and two pts had advanced melanoma. One pt in cohort 2 with refractory Hodgkin ’s disease progressed rapidly and was withdrawn from study. Drug-related adverse event data are available for nineteen patients. F ever (15 pts) and chills (10 pts) were common adverse events. Myalgia and nausea occurred in 3 and 6 pts, respectively. Hypotension with bradycardia, a dose-limiting toxicity occurred in 1 pt in cohort 4. This cohort was expanded to 6 pts with no further dose-limi ting
toxicities observed. Laboratory abnormalities during therapy included grade 1-2 neutropenia (9 pts), grade 1-3 lymphopenia (10 pts), grade 1-2 thrombocytopenia (3 pts), grade 1 increase in AST (4 pts), grade 1-2 increase in ALT (6 pts), grade 1 hypocalcemia (3 pts), and grade 1-2 hypoalbuminemia (11 pts). One pt each in cohorts 2, 4, and 5 developed low titer antibodies to IL-18; no pts in c ohorts 1 or 3 developed antibodies. Plasma concentrations of IL-18 increased less than proportionally with increasing dose. Daily dosi ng over 5 days resulted in approx. 2-fold accumulation, with an average elimination half-life of approx. 36 hours. Increases in ne opterin (18/19), GM-CSF (19/19), IL-18 BP (17/19), sFas/L(14/19), and INF³ (8/19) were observed. IL-12 was unmeasurable. Responses were observed in phenotypic markers of CD11b and FasL on NK cells, CD3/CD8/FasL, CD14/CD64, and CD8/CD69. Preliminary data demonstrate safety, tolerability and immunomodulatory activity of rhIL-18 administered as a single cycle.
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Update on the Clincial Development of GSK’s Dual ErbB Kinase Inhibitor Mark S. Berger, GlaxoSmithKline, Collegeville, PA
VEGF-Trap: A Novel VEGF Blocker with Potent Anti-Tumor Effects George Yancopoulos 1, Jocelyn Holash1, John Rudge1, Gavin Thurston1, Stanley Wiegand1, Nicholas Papadopoulos1, Sam Davis1, Jesse Cedarbaum1, Eugene Kim2, Jianzhong Huang2, Anna Serur2, Darrell Yamashiro2, Jessica Kandel 2. 1Research, Regeneron Pharmaceuticals, Inc., Tarrytown, NY; 2Division of Pediatric Surgery & Oncology, Columbia University, New York, NY.
The VEGFs works together with a series of other key growth factors, such as the Angiopoietins, during both blood and lymphatic vessel development. While the VEGFs are required for the initiation of vessel formation, Angiopoietins are critical during subs equent vessel maturation and stabilization. Consistent with these roles, vessels formed in the presence of excess VEGF are leaky and f ragile (and associated with tissue edema and hemmorhage), vessels made in the presence of excess Angiopoietin-1 are actually resistant to vascular leak induced by VEGF or inflammatory mediators. The discovery and characterization of multiple new angiogenesis regula tory factors is beginning to lead to a new understanding of the molecular basis of blood vessel development that seems likely t o have important therapeutic implications.
Re-examination of tumor angiogenesis, in the context of considering the roles of these various factors, reveals that tumor vess els are generally immature and unstable as compared to normal tissue vasculature, and that their initial sprouting as well as their con tinued maintenance depends largely upon VEGF as opposed to other growth factors, making the VEGF pathway the best validated target for anti-angiogenesis approaches in cancer. Indeed, recently reported clinical trials aimed at blocking VEGF using a humanized mono clonal antibody have shown exciting promise in cancer patients. We have engineered a very potent, high affinity VEGF blocker th at has extended pharmacokinetic properties, termed the “VEGF Trap”. In preclinical models, this VEGF-Trap effectively suppresses tumor growth and vascularization in vivo, resulting in stunted and almost completely avascular tumors, and can even cause tumor regression in certain cases. A Phase I clinical trial is currently underway with this agent.
The Proteasome Inhibitor Velcade™ Sensitizes Tumor Cells to Trail-Mediated Apoptosis Thomas Sayers 1, Alan Brooks1, Jennifer Onksen2, Peter Elliott 3, William Murphy4. 1SAIC Frederick. Inc., NCI Frederick, Frederick, MD; 2Laboratory of Experimental Immunology, NCI Frederick, Frederick, MD; 3Combinatorex, Boston, MA; 4
Department of Microbiology, University of Nevada, Reno, NV.
We have previously reported that the proteasome inhibitor VELCADE™ (PS-341) can sensitize a murine acute myeloid leukemia (C1498) and a murine renal cancer (Renca) to TRAIL-mediated apoptosis. The effects of VELCADE™ and TRAIL were selective, since this combination could purge C1498 tumor cells from bone marrow, without major effects on normal bone marrow cells. Surprisingly, sensitization of these murine tumor cells was independent of any effect of VELCADE™on NF-kB activation, yet did correlate with a reduction in levels of the anti-apoptotic protein c-FLIP. After transfection of c-FLIP, C1498 and Renca were m uch
more resistant to TRAIL-mediated apoptosis even following treatment with VELCADE™. VELCADE™ treatment also substantially increased cell-surface expression of the murine TRAIL receptor-2 (TRAIL-R2/DR5) -particularly on C1498 tumor cells. Therefore increases in TRAIL-R2, coupled with simultaneous decreases in c-FLIP, could result in a lowering of the molecular signaling thr eshold required for TRAIL-mediated apoptosis. Utilizing the NCI panel of 60 human tumor cell lines, we assessed the sensitivity of a wide variety of different human cancer cell lines to the combination of VELCADE™and TRAIL. A significant number of the tumor cell lines (20-30%) were dramatically sensitized to TRAIL-mediated apoptosis by treatment with VELCADE™ (20nM). However, for the remainder of the tumor cell lines, no such sensitization occurred. No obvious pattern emerged to account for these differen ces.
There was no apparent correlation for VELCADE™ sensitization with the tissue of origin of the tumor cells, their sensitivity to TRAIL as a single agent, or their p53 status. A more detailed analysis of 7 human renal cancer cell lines demonstrated a clear increase in the sensitivity of 3 renal lines to TRAIL following VELCADE™ treatment. For all 3 sensitized renal lines, c-FLIP levels were significantly reduced by PS-341 as assessed by western blotting. No changes in c-FLIP were seen in the remaining 4 renal cancer
lines. This data suggests that VELCADE™ can sensitize some human tumor cells to TRAIL-mediated apoptosis, and reduction in the levels of c-FLIP may be an important component of the molecular mechanism.
Funded in part by DHSS #NO1-CO-12400
New Agents in Development — continued
Program printing sponsored by
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Oral Abstracts
Efficacy and Tolerability of Interleukin 21 in a Mouse Model of Metastatic Melanoma Steve Hughes1, Richard Garcia1, Matthew Holdren1, Kim Waggie1, Andrew Nelson1, PV Sivakumar1, Monica Anderson1, Lucinda Yen1, Faith Shiota1, Don Foster1, Chris Clegg1. 1ZymoGenetics, Seattle, WA.
Interleukin 21 (IL-21) is a recently discovered class I cytokine produced by activated CD4 T cells. Its sequence and structure place it in the IL-2 family of cytokines, with greatest similarity to IL-2 and IL-15. Using mouse syngeneic tumor models, we have demonstrated the ability of IL-21 to reduce tumor growth through its ability to stimulate CTL and NK cell activity. In the B16F10 me tastatic melanoma model, mice developed significantly fewer lung tumors when treated with recombinant murine IL-21 (mIL-21), compared to control treated animals. Five daily injections of 75mg mIL-21 commencing on the day of tumor injection or 72 hours afterward s gave similar reductions in tumor burden. In addition, 2-3 times daily dosing with mIL-21 gave no improvement over once daily. Treatment with mIL-21 was well tolerated by mice, and despite its resemblance to IL-2, no evidence of IL-2-like side effects wa s observed. To further characterize pharmacological effects of mIL-21 in mice and to compare these with IL-2, we evaluated the ab ility of these two cytokines to elicit vascular leak syndrome (VLS), a well-characterized dose limiting side effect of IL-2 treatment . We administered a regimen of recombinant human IL-2 (rIL-2) known to produce VLS in mice or mass-equivalent doses of mIL-21 and measured resulting VLS, serum cytokine levels, and hematological parameters. The effects of rIL-2 were consistent with publishe d reports. Marked VLS was observed in both the lung and liver, along with dose-dependent increases in serum IL-5, TNFa and IFNg. Body temperature and weight were significantly decreased, as were circulating lymphocytes and platelets. In contrast, mIL-21 tr eated mice showed only mild VLS at the highest dose level. Compared to mice treated with rIL-2 at mass-equivalent doses, the extent o f VLS with mIL-21 treatment was more than 2-fold lower. No significant elevation in serum cytokines was observed with mIL-21 treatment. Body weight and temperature and hematological parameters were not significantly different from control animals. In summary, these two cytokines clearly exhibited distinct pharmacology in mice with regard to all study parameters. Although mIL- 21 treated mice developed mild VLS, other principal effects of IL-2 related to VLS development (e.g. cytokine release, lymphopenia ) were not observed with mIL-21 treatment. These collected findings suggest that IL-21 elicits a more selective immunomodulatory respo nse than that observed with IL-2. Because of the observed anti-tumor activity and relative absence of meaningful toxicity, we plan to initiate clinical studies with IL-21 in the first half of 2004, with metastatic melanoma and renal cell carcinoma as initial target indi cations.
A Phase II Study in Advanced Renal Cell Carcinoma of ABR-214936 (Anatumomab Mafenatox) Tumour Targeted Superantigen Therapy Robert E Hawkins 1, Noel B Connolly1, David Shaw1, Poulam Patel2, Carmel Garner1, D Beirne2, Suzanne Kilany3, Gunnar Hedlund3, Goran Forsberg3, Peter L Stern 1. 1Christie Hospital, Cancer Research UK Centre, Manchester, United Kingdom; 2Cancer Research UK
Clinical Centre, St James University Hospital, Leeds, United Kingdom; 3Active Biotech Research, Lund, Sweden.
Tumour Targeted Superantigen (TTS) therapy is a novel form of cancer therapy which involves targeting of the superantigen to si tes of tumour. The engineered superantigen is designed to produce strong activation of cytotoxic T cells in the tumour tissue. ABR-214 936 (anatumomab mafenatox) is a recombinant fusion protein of a mutated Staphylococcal enterotoxin A (SEA) and a Fab moiety recognising the oncofetal antigen, 5T4, which is expressed in the majority of patients with RCC.
In this sinlge arm phase II study patients with confirmed RCC, measurable disease and good performance status are treated with a daily 3-hour infusion of ABR-214936 for 4 consecutive days. Pre-formed circulating anti-SEA antibodies neutralise the effects o f ABR-214936 and therefore dosing is adapted to the pre-existing antibody-titre. Each patient is treated with an individual dose based on the pre-treatment anti-SEA antibody concentration and adjusted to body weight. A second cycle is given 4-6 weeks later at wh ich the dose is adjusted to the new anti-SEA titre. Patients are evaluated by means of a pre-treatment CT scan with repeat scan at D56 and
D112 to evaluate tumour response. If there is response then a 3 rd cycle may be given.
Side effects observed include pyrexia, rigors, nausea and vomiting, and hypotension. If a patient experience a drug-related AE/ SAE then the dose for the next infusion is decreased to 75% of that previously given, if there is a further reaction then the dose is reduced to 50% of the original. Treatment is well tolerated with only one patient withdrawn due to toxicity (grade 3 hypotension in first cycle). In
cycle one 30% (12/43 pts) required a dose reduction due to grade 1 or 2 toxicity and only one patient required a dose reduction in the second cycle of treatment. To date 39 patients out of 45 have reached D112 evaluation. The patient with maximum response has wa s treated second achieved a reduction in the measured size of the liver lesions by 90% after 3 cycles (PR by RECIST criteria on C T scan). This patient received ABR-214936 after progressing on interferon and after relaspe following hepatic resection. Approxim ately 36% of the evaluable patients have SD or better at the 4 month assessment. 4 patients have received 3 cycles of treatment.
ABR-214936 is a promising and active agent in advanced RCC. It has been demonstrated to be safe and well tolerated. The study h as now fully recruited and follow-up is ongoing.
New Agents in Development — continued
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Oral Abstracts
Update on the Evolution of the IMiD™
Jerome B Zeldis, MD, PhD, Robert Knight, MD, David Stirling, PhD. Medical Affairs, Celgene Corporation, Warren, NJ.
Thalidomide is a glutamic acid derivative that has generated renewed interest due to its activity in several forms of cancer. T halidomide is believed to function through multiple mechanisms including: angiogenesis inhibition, immunomodulation, mediation of cytokine levels, and reduced expression of cellular adhesion molecules. However, the exact mechanism of action has not been ful ly determined. Thalidomide has demonstrated clinical activity in refractory multiple myeloma, and the immunomodulatory effects observed provide a foundation for investigating the efficacy of thalidomide therapy in a many diseases including multiple myelo ma, MDS, and renal cell carcinoma. A novel class of rationally designed compounds called IMiDs has been designed as thalidomide analogues, with the intent of increasing immunomodulatory activity while minimizing adverse effects. Preclinical studies have demonstrated IMiDs are more potent than thalidomide at inhibiting tumor necrosis factor-a production, stimulating T-cell prolif eration
as well as interleukin-2 and interferon-g production. The antimyeloma activity of the IMiDs also involves sensitization of mult iple myeloma cells to apoptosis. In the clinical setting, administration of the lead IMiD CC-5013 has shown significant activity. A phase I study administering CC-5013 (5, 10, 25, and 50 mg/d) to patients with relapsed and refractory multiple myeloma resulted in a >25% reduction in paraprotein levels in 17 of 24 (71%) of patients, with no significant toxicities typically observed with thalidomi de treatment (i.e., somnolence, constipation, or neuropathy) in patients treated with 25 mg/d of CC-5013. Objective responses have also been reported with CC-5013 in a phase I trial of advanced melanoma and other solid tumors. Additionally, a recent phase I/II tr ial
examined the effect of CC-5013 on the erythroid response in patients with MDS. Treatment with CC-5013 demonstrated remarkable erythropoietic and cytogenic remitting activity in patients with MDS. Phase I and II studies are also evaluating another IMiD, CC4047, for the treatment of advanced multiple myeloma and genitourinary tumors.The immunomodulatory activity of thalidomide and the IMiD analogues have generated several ongoing studies assessing the antitumor activity of these agents (Table 1). CC-5013 h as
received fast-track status for the treatment of MDS and multiple myeloma and is also being assessed for the treatment of other hematologic malignancies and solid tumors.
Table 1. Ongoing trials of IMiDs in development*
IMiD Phase Disease
CC-5013 I Solid Tumors
I Glioma
I Lymphoma
I Refractory Metastatic Disease
II Myelodysplastic syndromes
II/III Multiple myeloma
II/III Progressive/relapsed malignant melanoma
CC-4047 I/II Relapsed/refractory multiple myeloma
II Prostate cancer
Compiled from the National Institute of Health (www.clinicaltrials.gov)
New Agents in Development — continued
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Natural Killer Cells & Innate Immunity
1 CD40 Ligation Induces Antitumor Reactivity of Murine Macrophages Via an Interferon Gamma-Dependent Mechanism Ilia N Buhtoiarov1,2, Hillary E Lum1, Paul M Sondel1,
Alexander L Rakhmilevich1. 1Department of Human Oncology and Comprehensive Cancer Center, University of Wisconsin, Madison, WI; 2I.N.B. Is Supported by the UICCAmerican Cancer Society Fellowship Grant for Beginning
Investigators (Geneva, Switzerland).
2 HMGB1 Promotes Macrophage Dependent Production of Interferon Gamma by Human NK Cells: Cellular Synergy Richard DeMarco 1, Mitchell Fink1 and Michael Lotze1.
1 Departments of Surgery, Critical Care Medicine, Bioengineering, University of Pittsburgh Molecular Medicine Institute, Pittsburgh, PA .
3 Cytotoxicity of IL-2 Activated Cord Blood Mononuclear Cells Stanka Derzic1, Vicki Slone1, Mike Schwartz1, Leonard Sender1. 1CHOC Research Institute, Cancer Research Lab,
Children’s Hospital of Orange County, Orange, CA.
4 A New Sequence Specific Primer (SSP) Assay for KIR Gene Detection David Dinauer 1, Cheryl Haas1, Erin McComb2, Lu Wang1. 1
Research and Development, Pel-Freez Clinical Systems, LLC, Brown Deer, WI; 2Marketing, Pel-Freez Clinical Systems, LLC, Brown Deer, WI.
5 Dendritic Cells Cocultivated with Autologous Peripheral Blood Lymphocytes Can Lead to Natural Killer Cell Outgrowth Jared Novak, Patric Schiltz, Sarah Hendry, Karen Spencer,
Linda Beutel, Robert Dillman. Cell Biology, Hoag Cancer Center, Newport Beach, CA.
6 Thermal Regulation of Granulocytes: A Role for Neutrophils in Tumor Growth Control Bradley Ertel1, Julie Lanphere1, William Kraybill2, Elizabeth Repasky1, Julie Ostberg1. 1Immunology, Roswell Park Cancer
Institute, Buffalo, NY; 2Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY.
7 Febrile Temperatures Regulate Nitric Oxide Production Michele Pritchard 1, Zhai Li2, Elizabeth Repasky1. 1Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY; 2School of Medicine, University of Connecticut,
Farmington, CT.
8 Rejection of Fas Ligand Positive Tumor Cells in Syngeneic Mice Is Dependent on T Cell Production of IFNGamma Rebecca Saff1, Andreas Hohlbaum2, Ann Marshak-
Rothstein1. 1Department of Microbiology, Boston University School of Medicine, Boston, MA; 2Pieris Proteolab AG, Freising-Weihenstephan, Germany.
9 CD34+ Cells Cultured in Stem Cell Factor and IL-2 Generate CD56+ Cells with Antiproliferative Effects on Tumor Cell Lines Giuseppe Sconocchia 1, Fujiwara Hiroshi, Rezvani Katayoun,
Keyvanfar Keyvan, El Ouriaghli Frank, Adams Mark, Hensel Nancy, Barrett John. 1Hematology, Allogeneic Stem Cell Transplantation, NHLBI, Bethesda, MD.
Dendritic Cells & Vaccines 10 MVA-MUC1-Il2 Vaccine Immunotherapy for MUC1Positive Cancer: Phase I and Interim Phase II Results Bruce Acres1, Rochlitz Christophe 2, Robert Figlin 3, Teresa
Maciejewska1, Brigitte Mourot 1, Patrick Squiban1, Nadine Faivre-Bizouarne1. 1Medical and Regulatory Affairs, Transgene, Strasbourg, France; 2Oncology, Kantonsspital, Basel, Switzerland; 3Urology, UC Los Angeles, Los Angeles,
CA.
11 CpG DNA: A Potent Stimulator of Dendritic Cells for Cancer Therapy Joseph Baar1, Quan Cai1, Luba Kublo1. 1Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA.
12 Three Previously Defined Epitopes from MAGE-A1, MAGE-A10, and GP100 Are Immunogenic when Combined with GM-CSF and Montanide-ISA 51 Adjuvant and Administered as Part of a Multi-Peptide Vaccine for Melanoma Kimberly A Chianese-Bullock 1, Jennifer Pressley 4, Sarah
Hibbitts4, Galina Yamshchikov1, Cheryl Murphy1, Gina R Petroni2, Eric Bissonette 2, Patrice Y Neese1, William W Grosh3, Priscilla Merrill 4, Robyn Fink4, Catherine J Wiernasz4, Elizabeth MH Woodson1, James Patterson5,
Courtney Garbee1, Craig L Slingluff, Jr 1. 1Surgery, University of Virginia, Charlottesville, VA; 2Health Evaluation Sciences; 3 Medicine; 4Cancer Center; 5Pathology, University of
Virginia, Charlottesville, VA.
Poster Session #1 – #64 (see Poster Abstract handout for complete abstracts)
Friday, October 31, 2003 – 12:00 pm – 1:30 pm
Poster #
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13 Immunopotentiating Reconstituted Influenza Virosomes (IRIV) Including PTH-rP Gene Plasmids (Gc90/IRIV) and PTH-rP Epitope Peptides as a Novel Cancer Vaccine Strategy Pierpaolo Correale 1, Maria Grazia Cusi2, Antonio Scardino3,
Lucia Micheli4, Francois A Lemonnier5, Rinaldo Zurbriggen6, Reinhart Gluck7, Giorgio Giorgi4, Guido Francini1. 1Section of Oncology, Department of Human Pathology and Oncology, Siena University School of Medicine, Siena, Italy; 2Microbiology Section, Department of
Molecular Biology, Siena University School of Medicine, Siena, Italy; 3INSERM U. 487, I.G.R., Villejuif Cedex, France; 4Department “G.Segre” of Pharmacology, Siena University School of Medicine, Siena, Italy; 5ICA, Institut
Pasteur, Paris Cedex 15, France; 6Pevion Corporation, Berne, Switzerland; 7Virology Department, Swiss Serum and Vaccine Institute, Berne, Switzerland.
14 Update on Cultured Autologous Tumor Cells and Dendritic Cells as Patient-Specific Vaccines in Recurrent or Metastatic Melanoma or Renal Cell Cancer R Dillman1, S Selvan1, P Schiltz 1, K Allen1, C DePriest1, A
Beatty1, C de Leon1, L Beutel1, C Peterson1, R Ellis 1. 1Hoag Cancer Center, Hoag Hospital, Newport Beach, CA.
15 A Wild Type CTL Epitope Encompasses a Natural Polymorphism at Codon 72 of P53: Implications for Vaccine Design and HPV-Associated Squamous Cell Carcinoma of the Head and Neck (SCCHN) Daisuke Ito1, Theresa Whiteside1, Albert DeLeo1, Robert
Ferris1,2. 1Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA; 2Otolaryngology and Immunology, University of Pittsburgh, Pittsburgh, PA.
16 Newly Defined Epitopes for Mouse Tyrosinase Demonstrate Potent Cd8+ T-Cell Responses to Xenogeneic Immunization with Tyrosinase Stacie M Goldberg 1, Jose A Guevara-Patino1, Stephanie C
Montgomery1, Miguel-Angel Perales1, Alan N Houghton1, Jedd D Wolchok1. 1Pediatrics and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY.
17 Preclinical Development of a Cellular Vaccine Using Dendritic Cells Pulsed with Tumor Derived Peptides Roy Guillermo1, Sun min Lee1, Maureen Loudovaris1, Aurelie Boyer2, Alessandra Nardin2, Nadege Bercovici2,
Marie-Therese Duffour2, Margarita Salcedo2, Jean-Pierre Abastado2, James Bender1. 1Scientific Operations, IDM, Inc., Irvine, CA; 2Scientific Operations, IDM Laboratoire de Recherche Luti, Paris, France.
18 Use of iTAg MHC Tetramers™To Monitor Vaccine Efficacy as Exemplified for Fluzone® Johannes Hampl 1, Ming Ye1, Jessica Novak1, Sumit Khurana1, Scott Schubert 1, Jyh-Feei Lin1, Suha Kasey1,
Kristine Kuus-Reichel1. 1Cell Analysis Development Center, Beckman Coulter, Inc., San Diego, CA.
19 Radiation Enhances Intratumoral Gene Therapy for Induction of Cancer Vaccine in Established Prostate Carcinoma Tumors Gilda G Hillman 1, Minzhen Xu2, Yu Wang1, Jennifer L
Wright1, Xueqing Lu2, Nikoletta L Kallinteris 2, Malcolm S Mitchell1, Jeffrey D Forman1. 1Radiation Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI; 2Antigen Express Inc., Worcester, MA.
20 Identification of a Novel Cancer/Testis Antigen Recognized by Melanoma Reactive Cytotoxic T Lymphocytes Kevin Hogan1, Michael Coppola2, Christine Gatlin 2, Lee Thompson1, Jeffrey Shabanowitz3, Donald Hunt3, Victor
Engelhard4, Mark Ross2, Craig Slingluff, Jr 1. 1Department of Surgery, University of Virginia, Charlottesville, VA; 2 Argonex, Inc., Charlottesville, VA; 3Department of Chemis-
try, University of Virginia, Charlottesville, VA; 4Department of Microbiology, University of Virginia, Charlottesville, VA.
21 Immunological Studies of Vaccine-Specific Responses in Breast and Prostate Cancer Patients Receiving a HER2/ Neu (E75) Vaccine Matthew Hueman 1, J Gurney1, C Storrer 2, L Kotula2, K
Jackson2, M Wilson2, D McLeod3, J Moul3, C Shriver1, S Ponniah2, G Peoples1. 1Clinical Breast Care Project, Walter Reed Army Medical Center; 2Uniformed Services University of the Health Sciences, Bethesda, MD; 3Center for Prostate
Disease Research, Walter Reed Army Medical Center, Washington, DC.
22 A New Concept for DNA Vaccine Development: Prolonging the Survival of DNA-Transduced Antigen Presenting Cells Chien-Fu Hung 1, Taewoo Kim1, TC Wc1. 1Pathology, Johns
Hopkins University, Baltimore, MD.
23 Vaccination of Rhesus Monkeys with Multi-Epitope Vaccine IGN402 Results in Immune Responses Against EpCAM and sialyl-Tn Carbohydrate Antigen Ralf Kircheis1, Petra Vondu1, Irene Zinocker1, Daniela
Haring1, Gunter Waxenecker1, Manfred Schuster1, Geert C Mudde1, Hans Loibner1, Gottfried Himmler1. 1Preclinical Research, Igeneon AG, Vienna, Austria.
Friday, October 31, 2003 – 12:00 pm – 1:30 pm Poster #
Poster Session #1 – #64 (see Poster Abstract handout for complete abstracts)
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24 Increasing the Number of Langerhans’ Cells (LC) in the Dermis as an Approach to Augmenting the Immunogenicity of Cancer Vaccines Keith L Knutson1, Carmen Berger2, Robert Underwood2, Lara
Muffley2, John Olerud2, Mary L Disis1. 1Tumor Vaccine Group, Division of Oncology, University of Washington, Seattle, WA; 2Division of Dermatology, University of Washington, Seattle, WA.
25 Peptide Vaccination Can Induce High-Frequency T Cell Responses and Long-Term Freedom from Relapsing Skin Metastases In Melanoma Anne Letsch1, Carmen Scheibenbogen1, Volker Mailaender1,
Anne Marie Asemissen1, Alexander Schmittel1, Eckhard Thiel1, Ulrich Keilholz 1. 1Hematology, Oncology and Transfusion Medicine, Charité, Campus Benjamin Franklin, Berlin, Germany.
26 Peptide Vaccination Induces Specific Effector and Memory Effector T Cells but Fails To Enhance Preexisting T Cell Immunity Anne Letsch1, Ulrich Keilholz 1, Volker Mailaender1, Dirk
Nagorsen2, Anne Marie Asemissen1, Eckhard Thiel1, Carmen Scheibenbogen1. 1Medical Clinic III,Hematology, Oncology and Transfusion Medicine, University Hospital Benjamin Franklin, Charité University Medicine Berlin, Berlin, Germany; 2Immunogenetics Section, Department of Transfu-
sion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
27 Comparison of the CD8+ T Cell Responses and Antitumor Effects Generated by DNA Vaccine Administered through Gene Gun, Biojector, and Syringe Cheng-Tao Lin 2,6, Cornelia Trimble1, Chien-Fu Hung2, Sara
Pi5, Jeremy Juang2, Liangmei He2, Maura Gillison3, Drew Pardoll3, Chyong-Huey Lai6, Ting-Chang Chang6, Lee Wu2, T-C Wu1,2,3,4. 1Departments ofr Obstetrics and Gynecology; 2
Pathology; 3Oncology; 4Molecular Microbiology and Immunology; 5Otolaryngology, The Johns Hopkins Medical Intitutions, Baltimore, MD; 6Department of Obs/Gyn, Chang Gung Memorial Hospital, Taipei, Taiwan.
28 The Quality of an Anti-HPV Specific Cellular Immune Responses Is Associated with the Nature of the Antigen Presenting Cell Markus Maeurer 1, Ingeborg Zehbe1, Hanni Hoehn1, Henryk
Pilch2, Kirsten Freitag 1, Claudia Neukirch1. 1Dept. of Medical Microbiology, University of Mainz, 55101 Mainz, Germany; 2Dept. of Gynecology and Obstetrics, University of Mainz, 55101 Mainz, Germany.
29 Serum-Free Generation of Type 1 Polarized DC: AlphaType-1 DC (ADC1) are Powerful Inducers of AntiCancer TH1 and CTL Responses Robbie Mailliard 1, Quan Cai1, Anna Kalinska1, Amy Wesa1, John Kirkwood2, Walter Storkus1, Pawel Kalinski1. 1Surgery,
University of Pittsburgh Cancer Insitute, Pittsburgh, PA; 2 Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA.
30 Activation of Dendritic Cells Prior to Intratumoral Injection Enhances Tumor Clearance Julie McEarchern, Alton Boynton, Marnix Bosch. Vaccine R&D, Northwest Biotherapeutics, Inc., Bothell, WA.
31 Adenoviral Transduction Efficiency and Phenotype of Human Monocyte-Derived Dendritic Cells Cultured with Either Fetal Calf Serum, Human Plasma, or Under Serum Free Conditions Brian Morrison1, Yoshio Sakai1, John Janik1, John Morris1.
1 Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
32 Activation of Tumor Antigen-Specific CTL by Myeloid DC Infected with an Attenuated Influenza A Virus Expressing a CTL Epitope Derived from the HER-2/Neu Proto-Oncogene James Murray 1, Clay Efferson2, Kouichiro Kawano2, Jeanne
Schickli3, Peter Palese 3, Adolfo Garcia-Sastre3, Constantin Ioannides2. 1Bioimmunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX; 2Gynecologic Oncology, The University of Texas MD Anderson Cancer
Center, Houston, TX; 3Microbiology, Mt. Sinai School of Medicine, New York, NY.
33 Polarized Macrophage Response to Cytokine Stimulation D Nagorsen1, E Wang1, V Monsurro1, F Marincola1, M Panelli1. 1Immunogenetics Section DTM, CC, NIH, Bethesda, MD.
34 Human Monocyte-Derived Dendritic Cells Demonstrate Altered Interleukin-12 Secretion in the Presence of Tumor Cell Lysates Dearbhaile M O’Donnell 1, Abigail E Turney1, Ruth M
Morgan1, Peter J Selby 1, Poulam M Patel1. 1Cancer Research UK Clinical Centre in Leeds, St James’s University Hospital, Leeds, W Yorkshire, United Kingdom.
35 Augmentation of Immune Response to HPV 16 E7 Using VLP-E7 Chimeric Fusion Protein with GM-CSF and Anti-CD40 in HLA-A2 Transgenic Mice Jiahua Qian1, Yujun Dong1, Yuk-ying S Pang1, Rami
Ibrahim1, Victor H Engelhand2, Jay A Berzofsky1, John T Schiller1, Samir N Khleif1. 1Experimental Transplantation Branch, Laboratory of Cellular Oncology, and Metabolism Branch, National Cancer Institute, National Institutes of
Health, Bethesda, MD; 2University of Vitginia, Charlottesville, VA.
Friday, October 31, 2003 – 12:00 pm – 1:30 pm Poster #
Poster Session #1 – #64 (see Poster Abstract handout for complete abstracts)
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36 -Tocopheryl Succinate Sensitizes Established Tumors to Vaccination with Non-Matured Dendritic Cells Lalitha Ramanathapuram, James Kobie, Emmanuel Akporiaye. Microbiology and Immunology, University of Arizona, Tucson, AZ; Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY; Microbiology and Immunology, University of Arizona, Tucson, AZ.
37 Indoleamine 2,3 Dioxygenase Expression and Activity in Dendritic Cells Karen Redlitz1, John Shannon2, David Munn3, Donna Deacon1, Craig Slingluff 1. 1Department of Surgery, Univer-
sity of Virginia, Charlottesville, VA; 2Biomolecular Core Facility, University of Virginia, Charlottesville, VA; 3Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA.
38 Phase II Trial to Explore the Influence of Concomitant Chemotherapies on the Immunogenicity of the Cancer Vaccine IGN101 in Patients with Epithelial Cancers Hellmut Samonigg 1, G Hofmann1, Th Bauernhofer1, M
Balic1, H Stoeger1, F Groiss, G Himmler, M Schuster, F Rosenkaimer, H Loibner2. 1Division of Oncology, Department of Internal Medicine, Karl-Franzens University, Graz, Austria; 2Igeneon AG, Wien, Austria.
39 A Phase I Clinical Trial of SYT-SSX Fusion GeneDerived Peptide to Patients with Synovial Sarcoma Yuriko Sato1, Satoshi Kawaguchi1, Yuki Nabeta1, Tomohide Tsukahara1, Kazunori Ida1, Satoshi Nagoya1, Takuro Wada1,
Toshihiko Yamashita1, Hideyuki Ikeda2, Toshihiko Torigoe2, Noriyuki Sato2. 1Orthopaedic Surgery, Sapporo Medical University, Sapporo, Hokkaido, Japan; 2Pahology, Sapporo Medical University, Sapporo, Hokkaido, Japan.
40 Tumor Lysate and Adjuvant Reactive Serum Antibodies Present in Melanoma Patients before and after Treatment with an Autologous Dendritic Cell Based Vaccine Patric Schiltz1, Sarah Hendry1, Jared Novak1, Gregory Lee1,
Robert Dillman1. 1Cell Biology, Hoag Cancer Center, Newport Beach, CA.
41 Phenotypic Analysis of In Vitro Generated Dendritic Cells Used To Support a Phase I/II Trial of Active Specific Immunotherapy for Metastatic Melanoma Patients Patric Schiltz1, Karen Spencer1, Gregory Lee1, Andrea
Beatty1, Jared Novak1, Linda Beutel1, Robert Dillman1. 1Cell Biology, Hoag Cancer Center, Newport Beach, CA.
42 Analysis of the Specificity of the Humoral Immune Response Induced by Cancer Vaccine IGN101 Manfred Schuster 1, Gottfried Himmler1, Hans Loibner1, Alois Jungbauer2, Astrid Duerauer2, Rainer Hahn2. 1Igeneon
AG, Immunotherapy of Cancer, Wien, Austria; 2Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Wien, Austria.
43 Establishment of Autologous Melanoma Cell Lines for Vaccine Therapy: Dynamic Assessment of Cell Line Feasibility Senthamil Selvan1, Jared Novak1, Andrea Beatty1, Linda
Beutel1, Robert Dillman1. 1Cell Biology, Hoag Cancer Center, Newport Beach, CA.
44 Exogenous Heat Shock Protein 90-Peptide ComplexesLoaded Dendritic Cells Efficiently Elicit Crosspresentation to Cytotoxic T Lymphocytes Yasuaki Tamura 1, Akihito Imai1, Toshihiko Torigoe1,
Noriyuki Sato1. 1Pathology, Sapporo Medical University, School of Medicine, Sapporo, Hokkaido, Japan.
45 Cloning of cDNA Encoding an Osteosarcoma Antigen Recognized by Autologous Cytotoxic T-Lymphocyte Clone Tomohide Tsukahara 1,2, Yuki Nabeta1, Satoshi Kawaguchi1,
Kazunori Ida1,2, Yuriko Sato1, Hideyuki Ikeda2, Toshihiko Torigoe2, Takuro Wada1, Toshihiko Yamashita1, Noriyuki Sato2. 1Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Hokkaido,
Japan; 2Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan.
46 Immature DC Cytokine Crosstalk: Combining IFNgð with IL-1 Enhances NfkðB Translocation and IL-12 Production but Inhibits CD80, CD83, and CD86 Expression Jukka Vakkila1, Richard DeMarco1, Michael Lotze1. 1Surgery,
Bioengineering, Molecular Medicine Institute, Pittsburgh, PA.
47 Injection of Tumor Cell/Nk Cell/Dc Mixture Induces an Increase in Number of Tumor-Specific Ctls in Lymph Nodes Draining the Injection Site and in Tumors on the Contra-Lateral Flank Qin Yang1, Steve Gooding1, Lisa Bailey1, Patricia Rice 1, Per
Basse1. 1University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA.
Friday, October 31, 2003 – 12:00 pm – 1:30 pm Poster #
Poster Session #1 – #64 (see Poster Abstract handout for complete abstracts)
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Adoptive Immunotherapy
48 RLIP76 (RALBP1) Mediates Doxorubicin Transport and Resistance in Lung Cancer Sanjay Awasthi, Sharad Singhal, Sushma Yadav, Jyotsana Singhal, Yogesh Awasthi. Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX; Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch at Galveston, Galveston, TX.
49 Redirected Specific Tumour Killing by Immune Cells through Chimeric FC-gð-Receptors Alireza Biglari1, David Gilham2, Lorna Woolford1, Leslie Fairbairn1. 1Gene Therapy Group, Paterson Institute for
Cancer Research, Manchester, United Kingdom; 2Medical Oncology Department, Paterson Institute for Cancer Research, Manchester, United Kingdom.
50 A Novel Technology for Large-Scale Expansion of Human CD4 T Cells Using Red Blood Cell-Conjugated Antibodies Vivek Chitnis1, Jayant Thatte 1, Lori Hipoloto1, Minh Vu1,
Yong-Xing Zhang1, Dawn Crover1, Surendra J Chavan1, Mohammad El-Kalay1, Dennis J Carlo1. 1Research and Development, Valeocyte Therapies LLC, San Diego, CA.
51 Trafficking and Clinical Responses in SCID-Beige Mice Bearing Her2/Neu-Positive Tumors Treated with Her2BiRetargeted Anti-CD3 Activated T Cells (ATC) Pamela A Davol 1, Jonathan Gall1, Sarah Olson1, Ryan C
Grabert1, Nicola M Kouttab1,2, Lawrence G Lum1,2. 1Adele R. DeCof Cancer Center, Roger Williams Hospital, Providence, RI; 2Dept. of Medicine, Boston University, Boston, MA.
52 Continuous Infusion Interleukin-2 and Antihistamines in Melanoma: A Retrospective Review Showing Activity of This Combination Maria Evangelista 1, Walter Quan, Jr2, Wendy Brick2,
Nawazish Khan2, Russell Burgess2. 1Department of Medicine, East Carolina University School of Medicine, Greenville, NC; 2Division of Hematology/Oncology, East Carolina University School of Medicine, Greenville, NC.
53 Clinical Commercialization of a Clonal Cell Line - NK92 Gary Keller1, Hans Klingemann1, Torsten Tonn1, Ann LeFever2, Michael Borys3, Matthew Palazzolo1, Richard Domanik1. 1Corporate Headquarters, ZelleRx Corporation,
Chicago, IL; 2Department of Immunotherapy, St. Luke’s Medical Center, Aurora Healthcare, Milwaukee, WI; 3Specialty Products Division, Abbott Laboratories, North Chicago, IL; 4Red Cross Blood Donor Service, Institute for
Transfusion Medicine and Hematology, Frankfurt, Main, Germany; 5Management of Medical Technology, Illinois Institute of Technology, Stuart Graduate School of Buisness, Chicago, IL.
54 Adjuvant Therapy with Activated T Cells for Patients with Renal Cell Carcinoma Ann LeFever1, Jonathan Treisman1, John Hanson, Jr1. 1
Immunotherapy Program, St. Luke’s Medical Center, Milwaukee, WI.
55 Yoyo-1 as a Measure of Tumor Cytolysis by Activated NK: Strategies for Evaluation of the Adoptive Immunotherapy of Cancer Patients Michael Lotze1, Stephen Winikoff2, Richard DeMarco1, Lina
Lu3, Herbert Zeh2, Jukka Vakkila1. 1Surgery, Molecular Genetics and Biochemistry, Bioengineering, Molecular Medicine Institute/University of Pittsburgh, Pittsburgh, PA; 2
Surgery, Division of Surgical Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA; 3Surgery, Starzl Transplant Institute, Pittsburgh, PA.
56 Fate and Function of Anti-Cd3 Activated T Cells (ATC) Armed with OKT3 X Anti-Her2/Neu Bispecific Antibody (Her2Bi) in Patients with Her2/Neu+ Tumors Lawrence Lum 1,2, Ryan Grabert1, Jonathan Gall1, Nicola
Kouttab1,2. 1Immunotherapy Program, Adele R.Decof Cancer Center, Roger Williams Hospital, Providence, RI; 2Department of Medicine, Boston University School of Medicine, Boston, MA.
57 Short-Term Ex Vivo Sensitization of Memory T Cells among PBMCs from Seropositive Subjects using CancerRelated Viral Peptides is Sufficient to Evaluate Immune Reactivity at a Molecular Level Maurizio Provenzano 1, Simone Mocellin2, Dirk Nagorsen1,
Francesco Marincola1, David Stroncek1. 1Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD; 2Surgery Branch, Department of Oncological and Surgical Science, University of Padova, Italy.
58 Repeated Cycles with 72-Hour Continuous Infusion Interleukin-2 in Kidney Cancer and Melanoma Walter Quan, Jr1, Mikhail Vinogradov2, Wendy Brick1, Russell Burgess1. 1Division of Hematology/Oncology, East
Carolina University School of Medicine, Greenville, NC; 2 Department of Internal Medicine, East Carolina University School of Medicine, Greenville, NC.
59 Continuous Infusion Followed by Pulse Interleukin-2 in Melanoma and Kidney Cancer Walter Quan, Jr1, W Chris Taylor2, Wendy Brick1, Russell Burgess1. 1Division of Hematology/Oncology, East Carolina
University School of Medicine, Greenville, NC; 2Department of Internal Medicine, East Carolina University School of Medicine, Greenville, NC.
Friday, October 31, 2003 – 12:00 pm – 1:30 pm
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60 Implementation of a Continuous Infusion (CIV) Interleukin-2 (IL-2) Regimen Program in a Teaching Hospital Walter Quan, Jr1, Wendy Brick1, Donna Copeland2, Russell
Burgess1. 1Division of Hematology/Oncology, East Carolina University School of Medicine, Greenville, NC; 2Cellular Therapy Unit, Pitt County Memorial Hospital, Greenville, NC.
61 Clinical Toxicities and Quality of Life Measures in Patients Receiving Infusions of T Cells Armed with OKT3 X Anti-Her2 Bispecific Antibody Wendy Young 1, Ritesh Rathore1,2, Gerald Colvin1, Mary
Falvey1, Ryan Grabert1, Jennifer Jarvis 1, Jonathan Gall1, Gerald Elfenbein1,2, Lawrence Lum1,2. 1Immunotherapy Program, Adele R. Decof Cancer Center, Roger Williams Hospital, Providence, RI; 2Department of Medicine, Boston
University School of Medicine, Boston, MA.
Pediatric Oncology 62 Phosphatidylserine-Dependent Suppression of Dendritic Cell Function by Neuroblastoma: A Novel Mechanism of Tumor Evasion
Xiao Chen1,2, Kara Doffek1,2, Erica Chan1, Claire Gavin1,2, Sonia Sugg1, Joel Shilyansky1,2. 1Department Surgery, Medical College of Wisconsin, Milwaukee, WI; 2Department of Surgery, Children’s Hospital of Wisconsin, Milwaukee, WI.
63 Fluorescence-Based In Vivo Models for Monitoring and Quantitating Cytokine- Or Chemotherapy-Induced Alterations in the Growth, Metastasis, Angiogenesis and Apoptosis of Neuroblastoma Tumors Jimmy K Stauffer1, Julie A Hixon1, Timothy C Back2, Erin
Lincoln2, Tahira Khan1, Jon M Wigginton 1. 1Pediatric Oncology Branch, NCI-CCR, Frederick, MD; 2IRSP, SAIC Frederick, Frederick, MD.
Imaging 64 A Comparison of Pharmacokinetic Modeling of Dynamic Contrast Enhanced MRI for Evaluating Response in Angiogenic Inhibitor Therapy
David Thomasson 1, Peter Choyke1, Andrew Dwyer1, Jack Yao 1. 1Diagnostic Radiology Department, NIH Warren G. Magnuson Clinical Center, Bethesda, MD.
Friday, October 31, 2003 – 12:00 pm – 1:30 pm Poster #
Poster Session #1 – #64 (see Poster Abstract handout for complete abstracts)
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Cytokines - Polymorphisms
65 The iTAg™ MHC Tetramer/Ifn- Assay Allows Enumeration of Tetramer Positive IFN- -Producing T Cells Judith Houlihan1, David Bossy2, Suha Kasey1, Roberto Renteria1, Christophe Le Boulaire 2, Lori Krueger1, Kristine
Kuus-Reichel1, Jennie Chang1. 1Cell Analysis Development Center, Beckman Coulter Inc., San Diego, CA; 2Beckman Coulter Inc., Marseille, Cedex, France.
66 Elements of the Cytokine Network in Multiple Myeloma Vito Michele Lauta 1. 1Dept of Biomedical Sciences and Human Oncology, Section of Internal Medecine and Clinical Oncology, Bari, Puglia, Italy.
67 Cytokine Induction of IL-24 in Human Peripheral Blood Mononuclear Cells Nancy Poindexter 1, Eugene Walch1, Sunil Chada2, Elizabeth Grimm1. 1Bioimmunotherapy, The University of Texas
M.D.Anderson Cancer Center, Houston, TX; 2Introgen Therapeutics, Inc., Houston, TX.
Angiogenesis 68 Tannic Acid is a Novel SDF-1a/CXCR4 Inhibitor with Potential Anti-Angiogenic Activity Xin Chen1, John A Beutler2, Joost J Oppenheim3, OM Zack
Howard3. 1The Basic Research Program, SAIC-Frederick,Inc, National Cancer Institute-Frederick, Frederick, MD; 2 Molecular Targets Discovery Program, National Cancer
Institute-Frederick, Frederick, MD; 3Laboratory of Molecular Immunoregulation, National Cancer Institute-Frederick, Frederick, MD.
69 Inhibition of Tumor Angiogenesis and Metastasis Via Downregulation of VEGF Signaling Pathway Jun Zhang1, Lisa Jennings1, Yi Lu1. 1Medicine, University of Tennessee Health Science Center, Memphis, TN.
70 Hydrodynamic Gene Delivery of Kringle-5 Domain of Plasminogen Suppresses Lung Metastasis in Mouse Renal Cell Carcinoma Morihiro Watanabe 1, Hiroshi Yazawa1, Timothy Back2,
Desirae Vasquez1, Natalia Bromberg1, Takaya Murakami3, Lynnette Shorts1, Jeff Subleski 1, Robert Wiltrout1. 1LEI, NCICCR, Frederick, MD; 2NCI-Frederick, Frederick, MD; 3LMI, NCI-CCR, Frederick, MD.
New Agents in Development 71 Characterization of the Resistance Mechanisms of HL60 Leukemia Cell Derivatives to Apo2l/TRAIL J Cheng1, BL Hylander1, M Baer2, EA Repasky1. 1Immunol-
ogy, Roswell Park Cancer Institute, Buffalo, NY; 2Medicine, Roswell Park Cancer Institute, Buffalo, NY.
72 Development of Anti-Gastrin Therapeutic Vaccine by Linear Array Technology Mei-Chen Chen 1, Chia-Tse Hsu1, Mei-Luen Yang1, ChunYuan Ting1, Ren-Shiang Lee1, Jaulang Hwang1,2. 1Institute of
Molecular Biology, Academia Sinica, Taipei, Taiwan; 2 Institute of Molecular Biology, College of Sciences, National Chung-Cheng University, Chia-Yi, Taiwan.
73 Peg-Liposomal Formulation with Linked Anti-DNMT1/ HDAC2 Bispecific Single-Chain Fv Molecules (bs-ScFv) and Encapsulated VRL Induces ADCC and Apoptosis in Advanced Breast CA (IDC) Characterised by HDAC2 Overexpression and 5'CpG Island Hypermethylation of TSGs John Giannios1, Emmanuel Michailakis2, Gregory
Xepapadakis3, Nick Alexandropoulos4. 1Dept.of Clinical Oncology, GSHA, Athens, Greece; 2Dept.of Clinical Oncology, GSHA, Athens, Greece; 3Dept.of Breast Surgery, MH, Greece; 4Dept.of Clinical Biochemistry, IH, Greece.
74 Immunotherapy Consisting of Vinorelbine Encapsulated in Pegylated Liposomes with Linked antiEGFR Chimeric Mabs (Sv/22-00) Exert Antiangiogenic Action and Induce ADCC,CMC, Anoikis and PCD in Chemoresistant Metastatic Choroidal Melanoma J. Giannios, E. Michailakis, N. Alexandropoulos, T. Kononas. Dept. of Clinical Oncology, GSHA; Dept. of Clinical Biochemistry, IH; Dept. of Surgery, IH, Athens, Greece.
75 Tumor Targeting of Tetravalent CH2 Domain-Deleted CC49 mAbs Scott Glaser1, Xiufeng Wu1, Gary Braslawsky1, Paul Chinn1, Tim Kazules1, Ron Morena1, Daniel Perret 1, Jennifer Hopp1,
Tzung-Horng Yang1, Mitchell Reff 1. 1Research and Product Development, IDEC Pharmaceuticals Corporation, San Diego, CA.
76 APO2L/TRAIL Suppresses the Growth of Surgical Specimens of Patient Pancreatic Tumors Grown in Scid Mice and This Effect Is Improved in Combination with Gemcitabine BL Hylander1, S Zafar2, R Pitoniak1, J Gibbs2, EA Repasky1.
1 Immunology, Roswell Park Cancer Institute, Buffalo, NY; 2 Surgery, Roswell Park Cancer Institute, Buffalo, NY.
Saturday, November 1, 2003 – 11:30 am – 1:00 pm
Poster Session #65 – #122 (see Poster Abstract handout for complete abstracts)
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Saturday, November 1, 2003 – 11:30 am – 1:00 pm
77 Biomarker Profile and Clinical Safety of S.C. or I.V. Doses of Promune™ (CpG 7909 Injection) a Novel TLR-9 Agonist Oligodeoxynucleotide Arthur Krieg1, Susan Efler1, Janet Price 1, Mohammed Al-
Adhami1, John Whisnant1. 1Drug Development, Coley Pharmaceutical Group, Wellesley, MA.
78 Time for a Change. Therapeutic Use of a Natural Molecule ( GBP) as a Selective Anti-Cancer Agent Livio Mallucci1, Valerie Wells1, Khew-Voon Chin2, Mark Lawler3, Renato Mariani4, Lavinia Lotti 4, Alba Minelli5. 1Life
Sciences, King’s College London, London, United Kingdom; 2 School of Pharmacy, Rutgers University, Piscataway, NJ; 3
Haematology, Trinity College, Dublin, Ireland; 4General Pathology, La Sapienza University, Rome, Italy; 5Biochemistry, Perugia University, Perugia, Italy.
79 Interleukin-13 Pseudomonas Exotoxin Therapy in Animal Model of Breast Cancer Koji Kawakami1, Mariko Kawakami1, Raj Puri1. 1Laboratory of Molecular Tumor Biology, Division of Cellular and Gene
Therapies, Center for Biologics Evaluation and Research, FDA, Bethesda, MD.
80 Tumor Suppression Induced by the Macrophage Activating Lipopeptide MALP-2 in an Ultrasound-Guided Pancreatic Carcinoma Mouse Model Christoph Schneider 1, Carsten Ziske1, Ingo Schmidt-Wolf1,
Peter F Mühlradt2, Angela Märten1,3. 1Dept. of Internal Medicine I, University of Bonn, Bonn, Germany; 2Wound Healing Research Group, BioTec-Gründerzentrum, Braunschweig, Germany; 3Dept.of Surgery, University of
Heidelberg, Heidelberg, Germany.
81 Purified Proteins from the Cartilage of Persian Gulf Shark Carchahrinus Sorrah Posses Antiproliferative Activity Against Mouse Fibrosarcoma Cells Ahmad Shariftabrizi 1, Fourazandeh Fereydooni2, Bijan
Farzami3, Mohammadreza Khoramizadeh1, Kamran Alimoghadam1, Khodadad Namiranian4, Behrooz Nikbin5, Mohsen Karami6. 1Hematology,Oncology and BMT Research Center, Tehran University of Medical Sciences, Tehran,
Tehran, Islamic Republic of Iran; 2Cancer Institute, Tehran University of Medical Sciences, Tehran, Tehran, Islamic Republic of Iran; 3Biochemistry, Tehran University of Medical Sciences, Tehran, Tehran, Islamic Republic of Iran;
4 Department of Pharmacology, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran; 5Department of Immunology, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran; 6Department of Orthopedic
Surgery, Tehran University of Medical Sciences, Teahran, Islamic Republic of Iran.
82 IL21 Stimulates Durable Tumor Immunity by Enhancing CTL Activation and Survival Pallavur Sivakumar 1, Adrianna Moroz2, Andrew Nelson1, Steve Hughes3, Monica Anderson1, Faith Shiota 1, Lucinda
Yen 1, Matt Holdren3, Don Foster4, Protul Shrikant 2, Christopher Clegg1. 1Immunology, Zymogenetics Inc, Seattle, WA; 2 Immunology, Roswell Park Cancer Institute, Buffalo, NY; 3
Pre-Clinical Development, Zymogenetics Inc, Seattle, WA; 4 Cytokine and Receptor Biology, Zymogenetics Inc, Seattle, WA.
83 Efficacious Tumor Inhibition Mediated by Sirna Targeted Inhibition of Human Gp96 in Xenograft Breast Tumors Yijia Liu1, Jun Xu1, Qingquan Tang1, Patrick Lu1, Martin Woodle1, Frank Xie1. 1Genomics and Drug Development,
Intradigm Corporation, Rockville, MD.
84 Effect of Albumin Fusion on the Biodistribution of Interleukin-2 Zhengsheng Yao 1, Weili Dai1, James Perry1, Martin Brechbiel2, Cynthia Sung1. 1Clinical and Preclinical Phar-
macology, Human Genome Sciences, Inc., Rockville, MD; 2 Radiation Oncology, National Cancer Institute, Bethesda, MD.
Antibody Therapy 85 Neu Antigen-Negative Variants Can Be Generated Following Neu-Specific Antibody Therapy in NeuTransgenic Mice
Keith L Knutson1, Bond Almand1, Yushe Dang1, Mary L Disis1. 1Tumor Vaccine Group, Division of Oncology, University of Washington, Seattle, WA.
86 Combination LEC/chTNT-3 Fusion Protein Immunotherapy and CD25+ T-Regulatory Cell Depletion Produces Complete Remission of Experimental Solid Tumors Jiali Li1, Robyn Arias1, Peisheng Hu1, Leslie A Khawli1,
Aihong Liu1, Alan L Epstein1. 1Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles, CA.
87 Fusion Protein B7.1/Nhs76 for The Immunotherapy of Solid Tumors Aihong Liu1, Peisheng Hu1, Leslie A Khawli1, Nan Zhang1, Robyn Arias1, Alan L Epstein1. 1Department of Pathology,
University of California, Keck School of Medicine, Los Angeles, CA.
Poster Session #65 – #122 (see Poster Abstract handout for complete abstracts)
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88 Preliminary Data from the Phase I Clinical Trial with IGN311, a Fully Humanized IgG1 Antibody Against Lewis Y Daniel Oruzio1, Gunter Schlimok1, Norbert Eller 2, Christoph
Aulmann1, Stefan Stranner 2, Gunter Waxenecker2, Oliver Scheiber2, Andreas Obwaller2, Gottfried Himmler2, Hans Loibner2, Geert C Mudde2. 1II. Medizinische Klinik, Zentralklinikum, Augsburg, Germany; 2Igeneon AG, Vienna,
Austria.
Cytokine-based Immunotherapy 89 Dynamic Changes of Specific T Cell Responses to Melanoma Correlate with IL-2 Administration Mads Hald Andersen, Julie Gehl, Sine Reker, Lars
Ostergaard Pedersen, Jurgen Becker, Poul Geertsen, Per thor Straten. Tumor Immunology Group, Danish Cancer Society, Copenhagen, Denmark; Department of Oncology, Herlev University Hospital, Herlev, Denmark; Department of Dermatology, University of Würzburg, Wurzburg, Germany.
90 High Carbonic Anhydrase IX Expression Predicts for Renal Cancer Response to IL-2 Therapy Michael Atkins1, David McDermott1, James Mier1, Eric Stanbridge2, Amanda Youmans1, Adam Polivy1, Meredith
Regan1, Christine Connolly 1, Sabina Signoretti 1. 1Renal Cancer Program-in-Development, Dana-Farber/Harvard Cancer Center, Boston, MA; 2Departments of Microbiology and Molecular Genetics, University of California Irvine College of Medicine, Irvine, CA.
91 Chemo-Immunotherapy of Colo-Rectal Cancer: Evidence of Drug Induced Antigen Specific Lymphocytes Immune-Response In Vitro and in Cancer Patients by Using Chemotherapy Followed by GM-CSF and IL-2 Pierpaolo Correale 1, Angelo Aquino2, Lucia Micheli3,
Cristina Nencini3, Maria Teresa Del Vecchio4, Marco La Placa1, Simona Messinese1, Anna Giuliani2, Maria Grazia Cusi5, Giorgio Giorgi3, Guido Francini1, Enzo Bonmassar2. 1
Section of Oncology, Department of Human Pathology and Oncology, Siena University School of Medicine, Siena, Italy; 2 Medical Oncology and Pharmacology Section, Department
of Neuroscience, University of Roma Tor Vergata, Rome, Italy; 3“Giorgio Segre” Department of Pharmacology, Siena University School of Medicine, Siena, Italy; 4Section of Pathology, Department of Human Pathology and Oncology,
Siena University School of Medicine, Siena, Italy; 55Section of Microbiology, Department of Molecular Biolog, Siena University School of Medicine, Siena, Italy.
92 Subclones of a Streptozotocin Induced Renal Cell Carcinoma as a New Model for Investigation of Treatments for Kidney Cancer M Eilene Gruys 1, Timothy Back2, William Murphy3, Lisabeth
Welniak3, Jeff Subleski 1, Robert Wiltrout1. 1Laboratory of Experimental Immunology, NCI-Center for Cancer Research, Frederick, MD; 2Intramural Research Program, SAIC-Frederick, Frederick, MD; 3Department of Microbiol-
ogy, University of Nevada Medical School, Reno, NV.
93 Biweekly Subcutaneous rIL-2 Plus Vinorelbine and Gemcitabine in Metastatic Renal Cell Carcinoma: Clinical and Biological Results Michele Guida 1, Addolorata Casamassima1, Margherita
Picciariello 1, Cristina Ranieri 1, Rosalia Bernardino1, Eleonora Montenegro1, Michele Quaranta1, Vito Lorusso1. 1 Clinical Oncology and Experimental Oncology, I.R.C.C.S.
Oncology Institute, Bari, Bari, Italy.
94 Expression of STAT1 and STAT2 in Malignant Melanoma Does Not Correlate with Response to IFN-Alpha Adjuvant Therapy Gregory Lesinski1, Daniel Valentino2, Abhik Ray
Chaudhury3, Michael Walker2, William Carson1,2. 1Human Cancer Genetics, The Ohio State University, Columbus, OH; 2 Surgery, The Ohio State University, Columbus, OH; 3
Pathology, The Ohio State University, Columbus, OH.
95 Induction of Anti-Colon and Pancreatic Tumor Responses in Mice by Albuleukin™, an Interleukin-2 (IL-2) / Human Serum Albumin Fusion Protein Robert Melder1, Jiamo Lu1, Evelyn Good1. 1Preclinical
Development, Human Genome Sciences, Inc., Rockville, MD.
96 Immunoembolization of the Hepatic Artery with Granulocyte-Macrophase Colony Stimulating Factor (GMCSF): A Novel Approach for Metastatic Uveal Melanoma Takami Sato1, Mizue Terai1, David Berd1, Michael J
Mastrangelo1. 1Medical Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA.
97 CD40 Signaling in Renal Cell Carcinoma Leads to Increased Cytokine Expression and Decreased Tumor Size Lynnette Shorts1, Timothy Back2, Bruce Blazer3, William
Murphy4, Robert Wiltrout5. 1Laboratory of Experimental Immunology, NCI-CCR, Frederick, MD; 2Laboratory of Experimental Immunology, SAIC, Frederick, MD; 3Department of Pediatrics, University of Minnesota, Minneapolis,
MN; 4Department of Microbioloby, University of Nevada Medical School, Reno, NV; 5Laboratory of Experimental Immunology, NCI-CCR, Frederick, MD.
Saturday, November 1, 2003 – 11:30 am – 1:00 pm
Poster Session #65 – #122 (see Poster Abstract handout for complete abstracts)
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98 Primary Mucosal Melanoma with Metastases Presenting as a Dental Abscess and Responding to Interleukin-2 Satvir Singh1, Walter Quan, Jr1, Wendy Brick1, Russell Burgess1. 1Division of Hematology/Oncology, East Carolina
University School of Medicine, Greenville, NC.
99 Neoadjuvant Outpatient Interleukin-2 in a Patient with Metastatic Kidney Cancer Celalettin Ustun1, Walter Quan, Jr2, Wendy Brick2, Armine Baltayan3, Russell Burgess2. 1Internal Medicine, East
Carolina University School of Medicine, Greenville, NC; 2 Division of Hematology/Oncology, East Carolina University School of Medicine, Greenville, NC; 3Department of Pathol-
ogy, East Carolina University School of Medicine, Greenville, NC.
100 An Evaluation of the Use of IL-1H4 Adenovirus To Induce Protein Production and Reduce Tumor Burden Mary Donahee1, Karen Kozarsky1, Deborah Welham 1. 1
Protein Agents and Human Gene Therapy, GlaxoSmithKline, King of Prussia, PA.
101 A Phase I Investigation of Dose-Intensive Intravenous IL12/Pulse IL-2 in Adults with Advanced Solid Tumors Jon Wigginton1, Cynthia Donovan1, Peter Choyke2, Robert Wiltrout3, John Janik4. 1Pediatric Oncology Branch, NCI-
CCR; 2Functional Tumor Imaging Group, Department of Radiology, Bethesda, MD; 3Laboratory of Experimental Immunology, NCI at Fredrick, Frederick, MD; 4Metabolism Branch, NCI-CCR.
102 Interleukin-2 (Proleukin®, Aldesleukin) Augmentation of NK-Mediated Antibody Dependent Cellular Cytotoxicity (ADCC) is Associated with Durable Expansion of NK CD16+CD56+ Immune Effector Cells in Non-Hodgkin’s
Lymphoma Patients Receiving Rituximab Kimberly Denis-Mize1, Barbara Tong1, William Larry Gluck2, Alan R Yuen3, Alexandra M Levine4, Mark Dayton5,6, Jon Paul Gockerman7, Jennifer B Lucas8, Sandra Milan1,
Deborah Hurst1, Susan E Wilson1. 1Chiron Biopharmaceuticals, Chiron Corporation, Emeryville, CA; 2 Cancer Center of the Carolinas, Greenville, SC; 3Stanford
University Medical Center, Stanford, CA; 4University of Southern California, Los Angeles, CA; 5Louisiana State Medical Center, Shreveport, LA; 6Parker Hughes Cancer Center, Roseville, CA; 7Duke University Medical Center,
Durham, NC; 8California Cancer Care Department, Greenbrae, CA,.
Mechanisms of Escape 103 Role of Reactive Oxygen Species (ROS) on Death Receptors Signaling Chulhee Choi1,2, Eunjoo Jeong1, Etty Benveniste2. 1Division
of Molecular Life Sciences and Center for Cell Signaling Research, Ewha Womans University, Seoul, Republic of Korea; 2Cell Biology, University of Alabama at Birmingham, Birmingham, AL.
104 Expression of FC Gamma Receptor IIB by Melanoma Cells Modulates Tumor Growth and Therapeutic Effect of Monoclonal Antibodies Joel FG Cohen-Solal, Lydie Cassard, Anshu Agarwal, Annie Galinha, Catherine Sautes-Fridman, Wolf Herman Fridman. Laboratoire d Immunologie Cellulaire et Clinique, INSERM U255 UPMC-P6, Paris, France.
105 FASL-Containing Microvesicles in the Circulation of Patients with Cancer Induce Apoptosis of Activated T Lymphocytes Jeong-Whun Kim 1, Eva Wieckowski1, Douglas Taylor2, Torsten
Reichert3, Theresa Whiteside1. 1Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, PA; 2Obstetrics and Gynecology, University of Kentucky, Lexington, KY; 3Oral and Maxillofacial Surgery, University of Mainz, Mainz, Germany.
106 Interleukin-12 Induces Type 1 Response of Regional Nodes with Paradoxical Systemic Type 2 Responses in Patients with Advanced Gastric and Colorectal Cancer Masahiko Shibata 1, Masayoshi Suzuki1, Hideo Abe1, Hisao
Kanou1. 1Department of Surgery, Nihon University School of Medicine, Itabashi, Tokyo, Japan.
107 Loss of T Cell Receptor Cd3zð-Chain by L-Arginine Depletion: Role in Renal Cell Carcinoma Arnold H Zea1, Michael B Atkins2, Joanna DeSalvo1, Kevin Zwesdaryk1, Claudia Hernandez1, Paulo Rodriguez1, Jovanny
Zabaleta1, Augusto C Ochoa1. 1Stanley S. Scott Cancer Center-Tumor Immunology Program, Louisiana State University HSC, New Orleans, LA; 2Harvard Medical School-Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA.
108 Immune Escape, Immune Editing, and Immune Adaptation in a Long-Term Survivor of Metastatic Melanoma Galina Yamshchikov 1, Lee Thompson1, David Mullins2, Soldano Ferrone3, Takeshi Ogino3, Chien-Chung Chang3,
Holly Galavotti1, Bill Aquila 1, Donna Deacon1, Bill Ross 4, James Patterson5, Victor Engelhard2, Craig Slingluff 1. 1 Department of Surgery, University of Virginia,
Charlottesville, VA; 2Dept of Microbiology, University of Virginia, Charlottesville, NY; 3Dept of Immunology, Roswell Park Cancer Institute, Buffalo, NY; 4Department of Medicine, University of Virginia, Charlottesville, VA; 5Department of
Pathology, University of Virginia, Charlottesville, VA.
Saturday, November 1, 2003 – 11:30 am – 1:00 pm
Poster Session #65 – #122 (see Poster Abstract handout for complete abstracts)
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Other
109 TCR Vbð-Restricted T Cells in the Peripheral Circulation and Tumor Infiltrating Lymphocytes of Patients with Cancer Preferentially Undergo Apoptosis Andreas Albers1, Takashi Tsukishiro1, Robert Ferris 1, Albert
DeLeo1, Theresa Whiteside1. 1Pathology, Otolaryngology and Tumorimmunology, University of Pittsburgh Cancer Institute, Pittsburgh, PA.
110 A Review of Some Cancer Clinical Trials with Montanide ISA 51 Vaccine Adjuvant Jerome Aucouturier 1, Stephane Ascarateil 1, Stephen O’Neill2. 1
Pharmaceutical Department, SEPPIC, Paris; 2Pharmaceutical Department, SEPPIC Inc, Fairfield, NJ.
111 Going beyond Peptide: Development of a Whole Protein Elispot Assay Mark Burkett1, Eric Derby1, Kimberly Shafer-Weaver1, Susan Strobl1, Tracy Ulderich1, Michael Baseler1, Anatoli
Malyguine1. 1Laboratory of Cell-Mediated Immunity, CSP, SAIC-Frederick, Inc., Frederick, MD.
112 HER-2/Neu Altered Peptide Ligand-Induced CTL Responses: Implications for Peptides with Increased HLA Affinity and T Cell Receptor Interaction Sara Dionne1, Margaret Smith2, Douglas Lake1. 1Microbiol-
ogy and Immunology, University of Arizona, Tucson, AZ; 2 Biochemistry, University of Arizona, Tucson, AZ.
113 Inhibition of Signalling Via Erb-B-Receptors by Antibodies That Target the Lewis Y-Antigen Markus Klinger 1, Hesso Farhan1, Michael Freissmuth1, Gottfried Himmler2, Evelyne Janzek2, Geert C Mudde2, Hans
Loibner2. 1Institute of Pharmacology, University of Vienna, Vienna, Austria; 2Igeneon AG, Vienna, Austria.
114 Establishment of Lentivirus-Mediated Double Suicide Gene System and Its Killing Effects on T Lymphocytes** Daoxin Ma1, Yirong Jiang1, Xueliang Chen1, Beihua Kong1, Ming Q Wei3, Chunsheng Liu1,2. 1Hematology, Qilu Hospital,
Shandong University, Jinan, Shandong, China; 2Molecular Medicine Program, Mayo Clinic, Rochester, MN; 3Gene Therapy Unit, The Prince Charles Hospital, Brisbane, Qld, Australia.
115 Elispot Assay Modifications in Immunological Monitoring Anatoli Malyguine 1, Susan Strobl1, Kimberly ShaferWeaver1, Eric Derby1, Mark Burkett1, Tracy Ulderich1,
Michael Baseler1. 1Clinical Services Program, SAICFrederick, Inc., NCI at Frederick, Frederick, MD.
Saturday, November 1, 2003 – 11:30 am – 1:00 pm
116 Mutant -Actinin-4: Specific Antitumor Immune Response and its Role in Cancer Development Fathia Mami-Chouaib, Jeanne Menez, Beatrice Lemaux Chansac, Dorothee Guillaume, Isabelle Vergnon, Faten El Hage, Salem Chouaib.
117 Multi-Center Experience with Novel Transplant Conditioning Regimens that Incorporate 90Y Ibritumomab Tiuxetan (Zevalin®) Radioimmunotherapy (RIT) for Autologous and Allogeneic Stem Cell Transplantation in
Patients with Poor-Risk B-Cell Non-Hodgkin’s Lymphoma (NHL): Targeted Intensification and Elimination of Total Body Irradiation A Molina1, A Nademanee2, JN Winter3, HC Fung2, DJ
Inwards4, P Multani1, I Khouri5, A Raubitschek2, CA White1. 1 Medical Affairs, IDEC Pharm., San Diego, CA; 2Department of Hematology/Bone Marrow Transplantation, City of Hope Cancer Ctr, Duarte, CA; 3Hematology/Oncology
Division, Northwestern Univ., Chicago, IL; 4Mayo Medical School, Mayo Clinic, Rochester, MN; 5Blood and Marrow Transplantation, MD Anderson Cancer Ctr, Houston, TX.
118 Radioimmunotherapy with Yttrium 90 Ibritumomab Tiuxetan (Zevalin®) Induces High Response Rates and Durable Remissions in Patients with Relapsed or Refractory B-Cell Non Hodgkin’s Lymphoma (NHL) JL Murray1, TE Witzig2, A Molina3, L Gordon4, C
Emmanouilides5, K Vo3, IW Flinn6, M Czuczman7, W Saville3, G Wiseman2, CA White3. 1Department of Bioimmunotherapy, MD Anderson, Houston, TX; 2Department of Hematology/Radiology, Mayo Clinic, Rochester,
MN; 3Medical Affairs, IDEC Pharm., San Diego, CA; 4 Hematology/Oncology Division, Northwestern Univ.,
Chicago, IL; 5Department of Medicine - Hematology & Oncology, UCLA, Los Angeles, CA; 6School of Medicine, Johns Hopkins, Baltimore, MD; 7Lymphoma/Myeloma Service, Roswell Park Cancer Inst., Buffalo, NY.
119 The Human Mena Protein, a Serex-Defined Antigen Overexpressed in Breast Cancer Eliciting Both Humoral and CD8+ T Cell Immune Response Francesca Di Modugno1, Giovanna Bronzi1, Matthew J
Scanlan2, Duilia Del Bello 1, Simona Cascioli1, Irene Venturo1, Claudio Botti 1, Maria Rita Nicotra 3, Marcella Mottolese1, Pier Giorgio Natali 1, Angela Santoni4, Elke Jager5, Paola Nisticò2. 1Experimental and Clinical Depart-
ment, Regina Elena Cancer Institute, Rome, Italy; 2Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY; 3Molecular Biology and Pathology, National Research Council, Rome, Italy; 4Experi-
mental Medicine and Pathology, University of Rome “La Sapienza”, Rome, Italy; 5Medizinische Klinik II, HamatologieOnkologie, Krankenhaus Nordwest, Frankfurt, Germany.
Poster Session #65 – #122 (see Poster Abstract handout for complete abstracts)
Poster #
56
www.isbtc.org
120 Quantification of Seven Matrix Metalloproteinases and Two Tissue Inhibitors of Metalloproteinases Using a Multiplexed Matrix Metalloproteinase Array Richard Noring1, Scott Van Arsdell 1, Christine Burns 1. 1
Research and Development, Pierce Boston Technology Center, Woburn, MA.
121 Comparative Analysis of Three Different Methods for the Detection of Disseminated Tumor Cells Andreas Obwaller 2, Marija Balic1, Alexander van der Kooi3, Nadia Dandachi1, Gottfried Himmler2, Geert C Mudde2,
Bernhard Peball2, Susanne Grunt2, Philipp Oberkleiner 2, Gerald V Doyle3, Leon WMM Terstappen3, Thomas Bauernhofer1, Hellmut Samonigg1, Hans Loibner2. 1Department of Clinical Oncology, University Hospital, Graz, Austria; 2Igeneon AG*, Vienna, Austria; 3Immunicon
Corp**, Huntingdon Valley.
122 Lewis Y / EpCAM Co-Expression in Breast Cancer Is Correlated with Poor Prognosis Guido Sauter1, Manfred Schuster2, Gottfried Himmler2, Geert C Mudde2, Hans Loibner2. 1Institute of Pathology,
University Basel, Basel, Switzerland; 2Igeneon AG, Vienna, Austria.
Saturday, November 1, 2003 – 11:30 am – 1:00 pm
Poster Session #65 – #122 (see Poster Abstract handout for complete abstracts)
Poster #
57
www.isbtc.org
Notes
58
www.isbtc.org
Notes
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Notes