E7 TCR-T cell therapy for HPV-associated cancers

PROJECT SUMMARY HPV-associated malignancies include cancers of the cervix, oropharynx, anus, vulva, vagina, and penis. They cause thousands of deaths in the United States each year. Treatments for metastatic disease rarely provide lasting palliation and have minimal curative potential. First-line therapy increasingly includes immune checkpoint blockade in combination with chemotherapy, limiting the options for subsequent treatment. Hence, there is a compelling need for more effective treatments for advanced-stage disease. HPV-associated cancers harbor the oncogenic HPV E6 and E7 proteins. These antigens are attractive targets for immunotherapy due to their uniform expression by tumors and absence of expression by healthy tissues. This expression pattern permits targeting the HPV oncoproteins without toxicity and with the intent to eliminate cancer cells and cure the patient. Specific immunotherapeutic targeting of HPV oncoproteins with cancer vaccines has not been effective, likely due in part to the reliance of vaccines on host T cells, which vary in precursor frequency and functional avidity. We have developed a new type of treatment for HPV-associated cancers that targets the E7 oncoprotein by administering high-avidity autologous T cells directed against E7 by a gene-engineered T-cell receptor (E7 TCR-T cells). E7 TCR-T cell therapy has demonstrated safety and clinical activity in treatment-refractory, metastatic HPV- associated metastatic cancers. In a phase I clinical trial, no dose-limiting toxicity was identified. Clinical activity included regression of widespread, bulky cancer and complete regression of most tumors in some patients – including immune checkpoint blockade-refractory tumors. Translational research identified immunomolecular mechanisms of resistance, which now permits for screening of patients to treat only those whose tumors demonstrate an absence of resistance markers. This project is for a two-center, phase II clinical trial of E7 TCR- T cell therapy for metastatic HPV-associated cancers. This trial will leverage the strengths of Rutgers Cancer Institute of New Jersey and the NIH Clinical Center to implement novel immunomolecular screening, next- generation (two-week) engineered T-cell manufacturing, and recruitment and treatment of patients from diverse geographic regions and backgrounds. The short-term goal of this research is to assess the response rate for E7 TCR-T cell therapy in the treatment of metastatic HPV-associated cancers. The long-term goal is to develop a new strategy to treat these malignancies with the aim of increasing survival and curing some patients. Aim 1 will determine the response rate for E7 TCR-T cell therapy by conducting the phase II trial. This research will also further characterize the safety profile of the treatment. Aim 2 will conduct transitional research to reveal the mechanisms by which E7 TCR-T cells mediate tumor regression and elucidate tumor evasion mechanisms that can guide next-generation therapeutic approaches and biomarker discovery.