Immune mechanisms underlie full therapeutic efficacy of a novel inhibitor of KrasG12D in mouse models of pancreatic ductal adenocarcinoma

Abstract The KRAS oncogene is mutated in greater than 90% of pancreatic ductal adenocarcinoma (PDAC) cases. MRTX1133 is a non-covalent inhibitor targeting the most common mutant KRAS in PDAC, KRASG12D, and has shown robust efficacy in various tumor models, including PDAC (Hallin et al., Nature Medicine, 2022; Kemp et al., Cancer Discovery, 2022). However, the interplay between MRTX1133 and the immune system has not been characterized. Using immunocompetent mouse models of PDAC, we aimed to elucidate whether the effects of MRTX1133 are immune dependent. Mice were injected subcutaneously with tumor cell clones derived from the autochthonous KPC mouse model of PDAC that reproducibly result in high or low levels of T cell infiltration. MRTX1133 suppressed tumor growth in both “T cell high” and “T cell low” tumor-bearing mice. However, complete regressions were observed only in mice bearing T cell high tumors (4/8 10d after treatment start), indicating that T cell abundance improves MRTX1133 efficacy. T cells were necessary for sustained tumor growth inhibition in both subcutaneous and autochthonous PDAC models, as mice depleted of CD4+ and CD8+ T cells demonstrated rapid tumor re-growth following cessation of MRTX1133. Batf3KO mice, which are deficient in cross-presenting dendritic cells, displayed reduced tumor control compared to wild type mice implanted with T cell high tumors. These data suggest that T cell priming is required to elicit MRTX1133’s complete anti-tumor activity. We also studied the impact of MRTX1133 on the tumor immune microenvironment. In the subcutaneous setting, T cell low tumor cells showed decreased proliferation (Ki-67+, P = 0.024) and increased apoptosis (CC3+, P = 0.022) after 36h of MRTX1133 treatment. T cell low tumor-bearing mice treated with MRTX1133 for 60h exhibited increased proportions of CD4+ (by 1.5-fold, P = 0.010) and CD8+ (by 2-fold, P = 0.004) T cells in the tumor. These tumor-infiltrating CD8+ T cells were more proliferative (Ki-67+, P < 0.001), activated (CD11a+, P = 0.006), and cytotoxic (GZMB+, P = 0.004) compared to corresponding T cells in vehicle-treated mice. Additionally, more CD8+ T cells in the tumor-draining lymph nodes of MRTX1133-treated mice were IFNγ+ (P < 0.001), illustrating a systemic immune effect from MRTX1133. Our findings indicate that T cells play an important role in MRTX1133’s demonstrated efficacy, suggesting a “vaccine effect” from mutant KRAS inhibition and offering a rationale for testing novel combinations of mutant KRAS inhibitors with cancer immunotherapies. Citation Format: Noah Cheng, Samantha B. Kemp, Nune Markosyan, Rina Sor, Il-Kyu Kim, Jill Hallin, Jason Shoush, Liz Quinones, Natalie V. Brown, Jared B. Bassett, Nikhil Joshi, Salina Yuan, Molly Smith, William P. Vostrejs, Kia Z. Perez-Vale, Benjamin Kahn, Feiyan Mo, Timothy R. Donahue, Caius G. Radu, Cynthia Clendenin, James G. Christensen, Robert H. Vonderheide, Ben Z. Stanger. Immune mechanisms underlie full therapeutic efficacy of a novel inhibitor of KrasG12D in mouse models of pancreatic ductal adenocarcinoma [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 6394.