Therapeutic HPV vaccines (PVX7) for Advanced Cervical Cancer

Project Summary/Abstract One of the major challenges for control of advanced cervical cancer is the identification, via a suitable biomarker, of treated patients who have residual disease and are at higher risk of developing recurrence and metastasis; and prevention of such disease recurrence and metastasis using innovative immunotherapies. The purpose of Project 4 is two-fold: 1) to conduct a pilot study of a new therapeutic HPV vaccine to determine its safety and tolerance in women who have completed standard-of-care therapy for cervical cancer and have no clinical evidence of cervical cancer, but potentially still carry minimal residual disease; and 2) to test whether cell-free HPV DNA (cfHPVDNA) in plasma provides a specific biomarker for the presence or persistence of HPV+ cancer. Our proposed adjuvant immunotherapy targets E6 and E7 of the two genotypes that cause > 70% of cervical cancer cases (HPV16 and HPV18). This immunotherapy comprises priming with a plasmid DNA (pBI-11) and boosting with a recombinant vaccinia virus (TA-HPV), a combination that elicits potent CD8+ T cell responses. The pBI-11 DNA encodes HPV16/18 E6-E7 protein linked to heat shock protein 70 (HSP70), a novel technology that profoundly enhances antigen presentation of these otherwise poorly immunogenic antigens. Previously, we showed that vaccination with pBI-11's predecessor, pBI-1 (which expressed only HPV16 E7 fused to HSP70), followed by intramuscular [IM] boost with TA-HPV, was safe and triggered histologic clearance in half of HPV16+ CIN2/3 patients. We further found that boosting with TA-HPV via skin scarification [SS] generated significantly better HPV antigen-specific CD8+ T cell-mediated immune responses. Thus, we hypothesize that after a priming IM vaccination with pBI-11 DNA, boosting with TA-HPV vaccinia via skin scarification will elicit a greater HPV-specific CD8+ T cell response than an IM boost, and can control minimal residual cervical cancer remaining after standard-of-care treatment (surgery and/or chemoradiation). Ultra-sensitive measurement of cfHPVDNA in plasma has promise as a biomarker to monitor cervical cancer disease burden, and identify individuals at high risk for disease recurrence after primary therapy. Our preliminary data suggest that a fully-automated, FDA-approved PCR-based test already used globally in screening can be readily adapted to measure cfHPVDNA in plasma. To test our hypothesis, we propose: (1) To assess the safety and feasibility of the pBI-11 DNA prime followed by TA-HPV boost (PVX7), wherein TA-HPV is administered via either IM injection or SS, in patients with advanced cervical cancer who have completed primary therapy and have no clinical evidence of disease; (2) To evaluate the systemic HPV16/18 E6/E7-specific cellular immune responses to PVX7 immunotherapy regimens with TA-HPV administered via IM or SS in patients with advanced cervical cancer who have completed primary therapy; and (3) To assess cell-free HPV16/18 DNA load in plasma pre- and post-PVX7 immunotherapy using different HPV genome detection methods, and characterize progression- free and overall survival for patients with advanced cervical cancer.