Abstract 5305: M9657, a tumor-targeted anti-CD137 agonist, induced significant antitumor immunity in combination with anti-PD-1 antibody

Abstract Background: M9657, a first-in-class tumor-targeted conditional immune agonist, was developed to boost antitumor immune responses in the tumor microenvironment (TME) by targeting CD137. The immune agonism potency of M9657 was validated through in vitro assays and in vivo efficacy studies in syngeneic tumor models using the surrogate antibody FS122m. Combining CD137 agonists and antiPD (L) -1 antibodies presents a novel therapeutic strategy to overcome immune checkpoint inhibitor (ICI) resistance and enhance antitumor activity via complementary mechanisms. Anti-PD- (L) -1 antibodies can reverse the suppressive immune signals, and CD137 agonists can boost T cell activation, improving antigen presentation and cytokine release. Methods: The antitumor immunity of M9657 + pembrolizumab (anti-PD-1 antibody) combination therapy was assessed using in-vitro luciferase and ex-vivo functional assays. In vivo antitumor efficacy was investigated with the M9657 surrogate (FS122m) and anti-mPD-1 in syngeneic tumor models expressing Mesothelin (MSLN). Results: The combination of M9657 and pembrolizumab displayed dose-dependent immune agonism potency and significantly enhanced tumor cell cytotoxicity and CD8+ T cell cytokine release relative to single agent treatments. In various syngeneic tumor models, the combination of FS122m with antimPD1 significantly increased antitumor efficacy relative to monotherapies, with more mice achieving complete tumor regression and prolonged median survival. Tumor-cured mice after combination treatment exhibited resistance to the primary tumor rechallenge, indicating the generation of tumor antigen-specific antitumor immunity and long-term immune protectivity. Conclusion: The combination of M9657 with anti-PD- (L) 1 could overcome primary ICI therapy resistance and improve the antitumor efficacy of current anti-PD- (L) 1 therapy in the clinic. Our findings support a combination strategy to combine M9657 with anti-PD- (L) 1 in a clinical setting, potentially leading to enhanced antitumor immunity and improved patient outcomes. Future studies should investigate the safety and efficacy of this combination therapy in human patients. Sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10. 13039/100009945) Citation Format: Chunxiao Xu, Sireesha Yalavarthi, Hong Zhang, Uma Mahesh Gundra, Clotilde Bourin, Laura Helming. M9657, a tumor-targeted anti-CD137 agonist, induced significant antitumor immunity in combination with anti-PD-1 antibody abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5305.