Abstract 720: Anti-OX-40 agonist antibody significantly increases therapeutic efficacy of TVGV-1 vaccine for HPV-positive cancers

Abstract

Abstract Background: Human papillomavirus 16 (HPV16) E7 protein is a potential target antigen for HPV-positive cancers due to its interaction with pRb tumor suppressor protein. The clinical-stage therapeutic vaccine, TVGV-1, comprises of the PE-E7-K3 fusion protein and the adjuvant GPI-0100, has shown therapeutic effect preclinically by stimulating T cell response targeting HPV16 E7 protein. TVGV-1 was well tolerated clinically in more than 30 HPV+ cervical intraepithelial neoplasia (CIN) patients. Agonistic antibodies targeting OX40 (CD134) have shown remarkable single agent anti-tumor effect by modulating T cell response surrounding tumor environment, as well as the ability to combine with other immunotherapies in several mouse tumor models. Here we evaluated the synergistic therapeutic potential of TVGV-1 vaccine combined with anti-OX-40 agonist antibody for HPV-positive cancer therapy. Methods: Therapeutic and immune efficacy of TVGV-1 in combination with anti-OX-40 agonist antibody was tested in E7 antigen expressing TC-1 tumor mouse model. Mice with various treatments were assessed for tumor growth and survival. Peripheral and tumor-infiltrating immune cell profiles with various treatments were also assessed by flow cytometry. Results: Our results revealed that both the HPV16 E7-specific humoral and cell-mediated immunities solely elicited by TVGV-1 vaccination was synergistically enhanced more than two-fold by concomitant anti-OX-40 agonist antibody treatment. In a TC-1 tumor model, tumor growth and overall survival was not protected by OX-40 antibody treatment alone, and mice was protected with prolonged survival benefit when treated in combination of TVGV-1 and OX-40 antibody. In TC-1 tumor bearing mice, about 10% decrease of peripheral CD3+ T cell was observed upon TC-1 tumor development, and restoration was only observed when mice were treated with combined TVGV-1 and OX-40 antibody. When tumor infiltrating lymphocytes recognizing HPV E7 antigen were prepared from these mice, the amount of tumor-infiltrating mononuclear cells and CD3+ T cells were dramatically increased with combination treatment when compared to control group or to treatment alone groups. Conclusions: We demonstrated efficacy with combination approach between TVGV-1 vaccine and anti-OX-40 agonistic antibody in a pre-clinically mouse model. This enhanced activity is likely due to modulation of T-cell population in tumor and in periphery. This result will guide to a better design to perform clinical studies in order to obtain better outcome with TVGV-1 cancer vaccine intended for treating HPV E7 bearing tumors. Citation Format: Yin-Ching Lin, Yi-Tsui Chiu, Yi-Chia Lin, Jiun-Ming Wu, Chien-Hung Chen, Wen-Fang Cheng, Chia-Mao Wu. Anti-OX-40 agonist antibody significantly increases therapeutic efficacy of TVGV-1 vaccine for HPV-positive cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 720.