Abstract 2744: Telomelysin-induced immunogenic cell death synergizes with anti-PD-1 antibody in non-immunogenic gastrointestinal tumors
Authors: Kanaya Nobuhiko , Kuroda Shinji , Morihiro Toshiaki , Kakiuchi Yoshihiko , Kubota Tetsushi , Kakiuchi Satoru , Nishizaki Masahiko , Urata Yasuo , Tazawa Hiroshi , Kagawa Shunsuke , Fujiwara Toshiyoshi 
Published: August 2018

Abstract
Background: Telomelysin (OBP-301) is a telomerase-specific oncolytic adenovirus, in which the telomerase promoter controls its replication and induction of cell death in human tumor cells. A FDA-approved phase I study has confirmed the safety and biological activity of intratumoral administration of Telomelysin in patients with advanced solid tumors in the US. Anti-programmed death-1 antibody (PD-1 Ab) has dramatically improved clinical outcomes for patients with melanoma or lung cancer; however, the clinical benefit is limited to small population of patients with certain degree of tumor infiltrating lymphocytes (TILs). Therefore, more effective strategy to enhance the immunogenicity of non-immunogenic tumors is needed. Here, we show the potential of our oncolytic adenovirus as an immunogenic agent sensitizing non-immunogenic gastrointestinal tumors to PD-1 Ab.
Methods: A murine colon cancer cell line CT26 (BALB/c) and a murine pancreatic cancer cell line PAN02 (C57BL/6) were used in this study. An OBP-301 variant (OBP-502) that expresses the RGD mutant fiber to infect murine tumor cells via interaction with integrin was used as an oncolytic adenovirus. PD-1 Ab (clone 4H2) was obtained from Ono Pharmaceutical Co. Ltd. As immunogenic cell death markers, extracellular ATP and high mobility group box 1 (HMGB1) levels were measured following OBP-502 infection. In vivo subcutaneous tumor models, CD8-positive TILs, vaccination efficiency of OBP-502-treated cells and combination therapy of OBP-502 with PD-1 Ab were evaluated.
Results: OBP-502 efficinetly killed CT26 and PAN02 cells, and also significantly increased extracellular ATP and HMGB1 on both cell lines in vitro, suggesting that OBP-502-induced cell death might be immunogenic. Indeed, in the CT26 and PAN02 subcutaneous tumor models, OBP-502 induced massive accumulation of TILs compared to control. Vaccination of mice with OBP-502-infected CT26 cells rejected tumors in three of 10 vaccinated mice (30%) and also significantly suppressed the growth of remaining seven CT26 tumors. The combination therapy of OBP-502 and PD-1 Ab significantly suppressed the growth of CT26 subcutaneous tumors and successfully eradicated tumors in four of 12 mice (33%) while either single treatment failed to eradicate in most mice. When these 4 tumor-free mice treated with the combination therapy were re-challenged by inoculation of CT26 cells, two of 4 mice (50%) remained tumor-free. Similar antitumor effects of the combination therapy were observed in the PAN02 tumor model.H.E staining of major organs harvested after each treatment demonstrated no serious systemic toxicity that PD-1 Ab has been reported to cause sometimes in clinical practice.
Conclusion: Our telomerase-specific oncolytic adenovirus has the potential to activate antitumor immunity, leading to sensitization of non-immunogenic gastrointestinal tumors to PD-1 Ab.
Citation Format: Nobuhiko Kanaya, Shinji Kuroda, Toshiaki Morihiro, Yoshihiko Kakiuchi, Tetsushi Kubota, Satoru Kakiuchi, Masahiko Nishizaki, Yasuo Urata, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara. Telomelysin-induced immunogenic cell death synergizes with anti-PD-1 antibody in non-immunogenic gastrointestinal tumors [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 2744.