Journal of Clinical Oncology, 2009 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 27, No 15S (May 20 Supplement), 2009: 3062
© 2009 American Society of Clinical Oncology
 

Abstract
 

Effect on humoral and cellular immunity and on apoptosis in CIN2, CIN3, and HPV16+ cervical cancer of therapeutic divalent genetic vaccination with CMV replicon system (CRS) delivering HPV16 recombinantly mutated E6 and E7 viral oncogenes targeting p53 and Rb, respectively
J. Giannios, J. Peristeris, N. Alexandropoulos, T. Kononas and P. Ginopoulos
Erasinio Oncology Hospital, Athens, Greece; Hellenic Institute of Gynaecology, Athens, Greece; I.Hospital, Athens, Greece; Saint Andreas Hospital, Patras, Greece

Background:Prophylactic vaccines have no therapeutic capacityfor all the women who are already infected with HPV16 and havedeveloped cervical intraepithelial neoplasia (CIN) or cervicalcancer. Approximately 300 million women with CIN and cervicalcancer will require therapy in the next decades. Thus, thereis a great demand for a therapeutic HPV vaccine. Methods: Wedeveloped a cytomegalovirus (CMV) replicon system (CRS) fordelivery of the HPV16 recombinantly mutated E6 and E7 genesreplacing part of the CMV genome for the HPV genes, which weregenetically altered to block binding sites for p53 and Rb.Thereplicon-vectors infected and co-transfected CIN and cervicalcancer cells in animal models derived from HPV16(+) CIN, andcervical Ca cells obtained from patients. The genetic vaccinewas administered subcutaneously (SC) with a needless injectionsystem. Results: After vaccination,the viral E6 oncogene didnot degrade apoptotic p53, and it blocked activation of telomerase.This induced apoptosis and DNA repair in CIN and cervical cancercells. Furthermore, the E7 viral oncogene did not degrade theretinoblastoma oncogene (Rb) protein releasing transcriptionfactor E2F. This vaccination led to scheduled cell cycle entry,genetic stability, and mortalization of tumor cells. Humoraland cellular immune responses were exhibited, which led to irreversibleD2 apoptotic stage of PCD type I leading to a bystander killingeffect of CIN, and cervical cancer cells. BrdU and MTT analysisexhibited inhibition of DNA synthesis and metabolic activityof vaccinated tumor cells compared to controls. Conclusions:This genetic divalent vaccine coding for E6 and E7 mutationsdesigned to prevent p53 and Rb binding sites activated humoraland cellular immune responses leading to apoptosis of CIN andcervical cancer cells. It is up to translational medicine tobring this therapeutic vaccine into the clinic for patientswith CIN2, CIN3, and cervical cancer patients.