Abstract 6405: T-cell dependency of tumor regressions and complete responses with RAS(ON) multi-selective inhibition in preclinical models of PDAC

Abstract Activating mutations in KRAS drive tumorigenesis in more than 90% of cases of pancreatic ductal adenocarcinoma (PDAC), promoting tumor cell proliferation and survival and contributing to an immunosuppressive tumor microenvironment (TME). RAS(ON) multi-selective inhibitors, such as RMC-6236 and RMC-7977, potently block the active state of mutant and wild-type RAS isoforms and show profound anti-tumor activity in PDAC murine models1. Here, we utilized a panel of immunocompetent mouse models of PDAC to evaluate the extent to which the adaptive immune system is required for the full anti-tumor effects of RAS(ON) multi-selective inhibitors. In implantable KrasG12D Trp53R172H Pdx1-Cre YFP (KPC/Y)-derived models, treatment with RMC-7977 led to rapid and profound regressions across models, including complete responses (CRs) in mice bearing tumors with high baseline levels of T cell infiltration. RMC-7977 reshaped the TME, decreasing myeloid cells and increasing T cells and macrophages after 72 hours of treatment. Interestingly, the depth and duration of tumor regression after treatment with RAS(ON) multi-selective inhibitors were significantly decreased upon T cell depletion or in tumor-bearing Batf3-/- mice, that lack cross-presenting dendritic cells, suggesting that T cells are key contributors to the durability of response. Furthermore, the combination of RAS(ON) multi-selective inhibitors with T cell-directed immunotherapy agents - especially regimens containing CD40 agonists - conferred deeper and more durable tumor regressions. Notably, in mice bearing tumors with low baseline levels of T cell infiltration that did not respond to immunotherapy, RMC-7977 alone resulted in 4/7 tumor regressions whereas the combination of RMC-7977 with CD40 agonist, anti-PD-1, and anti-CTLA-4 led to 10/10 tumor regressions, including 3/10 CRs. Similarly, combination with immunotherapy also enhanced the anti-tumor activity of RMC-7977 in the autochthonous KPC/Y model of PDAC. Although the RAS-MAPK signaling is essential to T cell function, incubation of pre-activated murine or human CD8+ T cells with RMC-7977 did not impede viability, activation, or proliferation in vitro. In addition, treatment of mice with RMC-7977 did not affect T cell responses to vaccination challenge in vivo. Overall, our preclinical data suggest that an adaptive immune response contributes to the anti-tumor effects of RAS(ON) multi-selective inhibitors in PDAC models, supporting clinical evaluation of the combination of RAS(ON) multi-selective inhibitors with immunotherapy. References:1Wasko UN, Jiang J, et al. Tumor-selective activity of RAS-GTP inhibition in pancreatic cancer. Nature 1-3 (2024) doi:10.1038/s41586-024-07379-z. Citation Format: Margo I. Orlen, William P. Vostrejs, Rina Sor, Jayne C. McDevitt, Samantha B. Kemp, Il-Kyu Kim, Adam B. Kramer, Nataliya Tovbis Shifrin, Nune Markosyan, Cynthia Clendenin, Mallika Singh, Elsa Quintana, Marie Menard, Robert H. Vonderheide, Ben Z. Stanger. T-cell dependency of tumor regressions and complete responses with RAS(ON) multi-selective inhibition in preclinical models of PDAC [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 6405.