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

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
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Special Emphasis Panel (ZRG1-AARR-E (81))
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Rodriguez-Chavez, Isaac R
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Etubics Corporation
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