Intratumoral Injection of Therapeutic HPV Vaccinia Vaccine Following Cisplatin Enhances HPV-specific Antitumor Effects

摘要

Despite theconventional treatments of radiation therapy and chemotherapy, the five-year survival rates for patients withadvanced stage cervical cancers remain low. Cancer immunotherapy has emerged as an alternative, innovative therapythat may improve survival. Here we utilize a preclinical HPV-16 E6/E7-expressing tumor model, TC-1,and employ the chemotherapeutic agent cisplatin to generate an accumulation of CD11c+ dendritic cells in tumor loci making it an ideal location for the administration of therapeutic vaccines. Following cisplatin treatment, we tested different routes of administration of a therapeutic HPV vaccinia vaccine encoding HPV-16 E7 antigen (CRT/E7-VV).We found that TC-1tumor-bearing C57BL/6 mice treated with cisplatin and intratumoral injection of CRT/E7-VV significantly increased E7-specific CD8+ T cells in the blood and generated potent local and systemic antitumor immune responsescompared to mice receiving cisplatin and CRT/E7-VV intraperitoneally or mice treated with cisplatin alone. We further extended our study using a clinical grade recombinant vaccinia vaccine encoding HPV-16/18 E6/E7 antigens (TA-HPV).We found that intratumoral injection with TA-HPV following cisplatin treatment also led to increased E7-specific CD8+ T cells in the blood as well as significantly decreased tumor size compared to intratumoral injection with wild type vaccinia virus. Our study has strong implications for future clinical translation using intratumoralinjection of TA-HPV in conjunction with the current treatment strategies for patients with advanced cervical cancer.