Abstract 954: Preoperative p53-armed oncolytic virus therapy enhances the efficacy of postoperative adjuvant ICI therapy

Abstract Background: In recent years, the importance of perioperative treatment in cancer therapy has increased, and postoperative adjuvant therapies using immune checkpoint inhibitors (ICIs) have been applied clinically in multiple cancer types. However, the efficacy of ICIs as monotherapy is often limited. We have developed a telomerase-specific oncolytic virus (OV), OBP-301, and its p53 gene-armed derivative, OBP-702. OBP-301 is currently undergoing clinical trials. Previous studies have demonstrated enhanced antitumor immunity, including an increase in CD8+ T cells following OV administration. This study investigates the combination effect of preoperative OV therapy and postoperative adjuvant ICI therapy. Methods: Experiments were conducted using C57BL/6 mice implanted with MC38 colon cancer cells (p53 mutant/MSI-H) and PAN02 pancreatic cancer cells (p53 wild/MSS). OBP-702 was used as the OV, and anti-PD-1 antibody was used as the ICI. A subcutaneous tumor model in mice was employed to evaluate the therapeutic effects and immune responses using flow cytometry under a protocol combining preoperative OV therapy and postoperative ICI therapy. Additionally, Bulk RNA sequencing was performed to further analyze the mechanisms of enhanced antitumor immunity. Results: The OV-treated group exhibited significantly enhanced antitumor effects compared to the PBS-treated group. Analysis of tumor-infiltrating lymphocytes (TILs) in MC38 tumors revealed an increase in resident memory CD8+ T cells, PD-1+ CD8+ T cells, and p15E tetramer+ CD8+ T cells. Ex vivo CTL assays showed that TILs induced by OV exhibited stronger tumor specificity and antitumor activity. Additionally, in the OV group, p15E tetramer+ CD8+ T cells persisted significantly in the spleen for three weeks following primary tumor resection. In a rechallenge model where new tumors were established after tumor resection, preoperative OV therapy was shown to suppress postoperative recurrence and tumor growth while enhancing the effect of postoperative ICI therapy. Bulk RNA-seq of OV treated MC38 tumor with reactome pathway analysis revealed the upregulation of pathways associated with enhanced antitumor immunity. Conclusion: OV therapy not only demonstrated direct antitumor effects but also induced tumor-specific systemic immunity and sustained long-term immune activation. These results suggest that preoperative OV therapy can enhance the effectiveness of postoperative ICI therapy. Citation Format: Daisuke Kadowaki, Shinji Kuroda, Makoto Matsumoto, Hitoshi Minagi, Tetsuya Katayama, Yu Mikane, Shunya Hanzawa, Masashi Hashimoto, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Satoru Kikuchi, Kazuhiro Noma, Hiroshi Tazawa, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara. Preoperative p53-armed oncolytic virus therapy enhances the efficacy of postoperative adjuvant ICI therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 954.