The objective of this project is to further develop an immunotherapeutic strategy for HIV-associated malignancy based on the role of HPV in the pathogenesis and perform the pre-clinical experiments with a new drug which allow us to enter clinical trials to test its safety and effectiveness. HPV related cancers express the E6/E7 oncoproteins of HPV that are ideal targets for immune inducing vaccines. We developed a vaccine based upon a novel adenovirus serotype-5 vector (Ad5) platform with unique and additional deletions of the viral DNA polymerase and the pre-terminal protein in the early gene 2b (E2b) region (Ad5 [E1-, E2b-]). In studies employing infectious disease and cancer antigens, we reported that new Ad5 [E1-, E2b-] vector vaccines are superior to current Ad5 [E1-] vector vaccines (containing deletion in the early gene 1 (E1) region) when used to induce CMI responses in a multiple homologous immunization regimen. We have demonstrated that significant antigen specific CMI responses are induced in mice and monkeys despite the presence of pre- existing Ad5 immunity. Our data indicates that the new Ad5 [E1-, E2b-] vectors induces robust CMI responses against tumor associated antigens (TAA) resulting in anti-tumor activity, even in the presence of pre-existing Ad5 immunity. We have constructed and produced a modified HPV-E6/E7 gene that expresses non-oncogenic early gene 6 (E6) and early gene 7 (E7) HPV proteins. We have incorporated this modified HPV-E6/E7 gene into the new recombinant Ad5 [E1-, E2b-] vector platform (Ad5 [E1-, E2b-]-HPV-E6/E7) to be used as an immunotherapeutic for the treatment of patients with HPV-E6/E7 expressing cancers. This recombinant platform induces immune responses by expressing the modified HPV-E6/E7 antigens after direct transfection of antigen presenting cells via injection. We evaluated this dru combination with a toll-like receptor agonist (TLRa) platform designed to enhance immune responses induced by the vector. In an Ad5 immune murine cancer model employing the modified HPV-E6/E7 gene insert, the immunogenicity and in vivo anti-tumor effects of repeated immunizations with the Ad5 [E1-, E2b-]-HPV-E6/E7 with or without the addition of Ad5 [E1-, E2b-]-TLRa were compared. Significantly higher levels of HPV-E6/E7 directed CMI activity was induced in mice immunized with Ad5 [E1-, E2b-]-HPV-E6/E7 plus Ad5 [E1-, E2b-]-TLRa as compared with mice immunized with Ad5 [E1-, E2b-]-HPV-E6/E7 alone. Importantly, mice treated by immunotherapy with Ad5 [E1-, E2b-]-HPV-E6/E7 with or without the addition of Ad5 [E1-, E2b-]-TLRa experienced large reductions in tumor growth as compared with control mice injected with Ad5 [E1-, E2b-]-null (empty vector). These results indicate that immunotherapy of HPV-E6/E7 expressing tumors using the new Ad5 [E1-, E2b-]-HPV-E6/E7 induces potent anti-tumor activity. Our previous research data also indicates that this new immunotherapeutic drug may be used in conjunction with chemotherapy/irradiation treatment to induce effective anti-tumor activity. The studies in the present pre-clinical program will allow us to advance manufacturing approaches and acquire data that will allow us to advance to FDA approved clinical trials
In this study, we will develop a new immunotherapy to treat HPV induced cancers such as oropharyngeal and tonsillar cancers as well as certain cervical cancers. The new approach is to use an adenoviral based drug (Ad5 [E1-, E2b-]-HPV-E6/7) to treat HIV+ patients with HPV-associated Head and Neck cancers. Our published research data indicates that this novel immunotherapeutic drug induces anti-tumor activity and may be used in conjunction with chemotherapy/irradiation treatment for patients. These studies set the stage for a first in man clinical trial to test this approach in HIV+ Head and Neck cancer.
|Rice, A E; Latchman, Y E; Balint, J P et al. (2015) An HPV-E6/E7 immunotherapy plus PD-1 checkpoint inhibition results in tumor regression and reduction in PD-L1 expression. Cancer Gene Ther 22:454-62|