Abstract 2685: Synergistic antitumor effect of oncolytic virus and cytotoxic chemotherapy in gastric cancer

Abstract

Abstract Introduction: The prognosis of advanced gastric cancer is extremely poor, and the development of novel effective treatment is necessary. Currently, platinum-based, fluoropyrimidine-based, and paclitaxel-based combinations are accepted worldwide as established first-line and second-line drug regimens. Pexa-Vec (pexastimogene devacirpvec; JX-594) engineered from the Wyeth vaccine strain has emerged as attractive oncolytic virotherapy in cancer treatment. Pexa-Vec demonstrated oncolytic, immunotherapeutic, and tumor vascular disrupting mechanisms of action. The aim of this study is to investigate the combination efficacy of JX-594 with paclitaxel in human gastric cancer cell lines and to identify potential biomarkers of oncolytic virotherapy. Method: The anti-proliferative activities of paclitaxel and JX-594 were performed using 49 human gastric cancer cell lines, and YCC-32 was selected for sensitive to JX-594 and resistance to paclitaxel. YCC-32 was treated with JX-594 and paclitaxel, alone and in combination. Cytotoxicity was evaluated by MTT assay. Compusyn and Combenefit software was used to evaluate synergistic efficacy. In addition, the synergism effect was evaluated in the xenograft mouse model in vivo. Tumors were implanted by subcutaneous injection of 5 x 106 YCC-32 cells into the right flank of nude mice. When tumors reached >100mm3, mice were treated with either PBS, 1 x 107 plaque-forming units (pfu) of JX-594 by intratumoral (IT), 5mg/kg paclitaxel by intraperitoneal (IP) injection, or combination every 7 days. Result: Cytopathic effect of Pexa-Vec and paclitaxel was observed in YCC-32 gastric cancer cell line. IC50 (half maximal inhibitory concentration) of JX-594 and paclitaxel were 0.0089 MOI and 7.021ng/ml in YCC-32 cell. JX-594 and paclitaxel in YCC-32 was used to assess the synergism of the two drugs in a dose-dependent manner. In YCC-32 cell line, in combination with JX-594 0.01 MOI and paclitaxel 7ng/ml had CI (combination index) value had 0.69, suggesting synergism. To assess the potential therapeutic benefit of combining JX-594 with paclitaxel in vivo, we employed YCC-32 xenograft models and observed the antitumor effects of JX-594, paclitaxel, and their combination. Paclitaxel, JX-594, and their combination reduced tumor growth compared to control at 64.1%, 59.2%, and 19.1% for YCC-32 xenografts. This result suggests that combined treatment with JX-594 and paclitaxel significantly enhanced tumor growth inhibition compared to monotherapy. Conclusion: Combination with JX-594 and paclitaxel showed enhanced antitumor effects in vitro and in vivo. This study shows combination synergism and provides a promising approach to combination therapy with an oncolytic virus on gastric cancer. For future research, additional studies on other gastric cancer cell lines and investigation of mechanisms are needed. Citation Format: Jee Hung Kim, YeLin Kim, Youkeun Shin, Dagyo Oh, Woo Sun Kwon, Tae Soo Kim, Namhee Lee, Keunhee Oh, Hyun Cheol Chung, Hei-Cheul Jeung, Sun Young Rha. Synergistic antitumor effect of oncolytic virus and cytotoxic chemotherapy in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2685.