Oncogenic human papilloma virus (HPV) is directly responsible for 5% of the world's cancer burden. HPV has been etiologically implicated in virtually all cases of cervical carcinoma and is increasingly responsible for head and neck cancers in the developed world with strains 16 and 18 considered high risk. Recently it was estimated that there were over half a million new cases of cervical cancer worldwide and in the same year this disease was projected to claim over 250,00 lives, making it the third most prevalent and fourth most lethal non- skin tumor in women. Current standard of care for advanced cervical carcinoma and head and neck cancers involve chemo-radiation with or without prior surgical resection resulting in significant morbidity without guaranteed cure. Screening programs and prophylactic vaccination are reducing the incidence of some HPV induced tumors, however lack of compliance and unvaccinated populations mean that significant illness and mortality still exists. We therefore sought to develop a novel pre-clinical immunotherapeutic for HPV induced cancers. An oncolytic vaccination strategy utilizing an attenuated Maraba MG1 rhabdovirus expressing inactive HPV antigens based on the E6 and E7 transforming proteins of strains 16 and 18 has been designed (MG1 E6E7). The TC1 cell line, which is a C57BL/6 syngeneic murine HPV cancer model, was acquired. Specific anti-E7 CD8+ T cell responses have been induced after oncolytic vaccination of mice generating sterilizing immunity against future engraftment with TC1 cells. Oncolytic vaccination of tumor free mice has generated between 24 and 50 million, combined blood and splenic CD8+ T cells per mouse, determined by interferon gamma production in response to a single E7 peptide quantified using intracellular staining and flow cytometry. Primed mice, boosted with MG1 E6E7 develop long lasting, marked and specific immunity against E7 and to a lesser extent E6. The prime: boost regimen has therapeutic efficacy against established subcutaneous TC1 tumors (mean volumes of 250 mm3) resulting in durable cures in this model. Depletion of CD8+ T cells impairs the activity of the vaccination protocol supporting the key role of cytotoxic lymphocytes in our treatment regimen. The data generated here support the pre-clinical activity of this oncolytic vaccination and pave the way for future clinical trials for the treatment of advanced metastatic HPV induced carcinomas.
Citation Format: Matthew J. Atherton, Kyle B. Stephenson, Yonghong Wan, David F. Stojdl, Brian D. Lichty. Oncolytic vaccination for HPV induced cancer. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B096.