Abstract B104: Pharmacological RAS inhibition synergizes with CAR T cells for tumor killing
Jayne C. McDevitt, Feiyan Mo, Connor J. Hennessey, William B. Sullivan, Cynthia Clendenin, Il-Kyu Kim, Sydney M. Shaffer, Max M. Wattenberg, Robert H. Vonderheide, Carl H. June, Ben Z. StangerAbstract
Background:
Despite the success of chimeric antigen receptor (CAR) T cell therapy for liquid cancers, it has provided minimal clinical benefit in solid cancers, including pancreatic ductal adenocarcinoma (PDAC). We have previously shown that pharmacological RAS inhibition favorably remodels the PDAC tumor immune microenvironment. Hence, we sought to determine whether RAS inhibition could make PDAC tumors more responsive to CAR T cell therapy.
Approach:
Using xenograft and syngeneic mouse models of PDAC, we tested the impact of a RAS(ON) multi-selective inhibitor RMC-6236 and a KRAS G12D-selective inhibitor MRTX1133 on the anti-tumor activity of PDAC-targeting CAR T cells. Forward genetic screens, transcriptome analysis, and immunostaining were used to define mechanisms of combinatorial activity.
Results:
Tumor-bearing mice treated with CAR T cells and RMC-6236 exhibited potent anti-tumor responses that markedly exceeded those observed with either monotherapy. For example, in a subcutaneous AsPC-1 xenograft mouse model, 0 of 8 animals receiving mesothelin-targeting human CAR T cells alone and 0 of 7 receiving RMC-6236 alone exhibited regressions at the day 45 endpoint. In contrast, 7 of 9 combination therapy-treated mice exhibited complete or near-complete responses at endpoint. The combinatorial benefits were recapitulated in vitro, where synergy modeling indicated strong synergy (Bliss synergy score >10) between CAR T cell therapy and RMC-6236 across 6 human and mouse PDAC models and 5 CAR designs. Synergy derived from a tumor cell-intrinsic effect, whereby inhibition of RAS signaling exclusively in cancer cells using MRTX1133 sensitized them to CAR T cell killing to a similar extent as RMC-6236. CRISPR screening to identify underlying mechanisms nominated tumor STAT1, a canonical mediator of the interferon response, as a driver of synergy. RAS inhibition resulted in increased phosphorylation of STAT1 at sites necessary for nuclear translocation and transcriptional activity. Accordingly, gene set enrichment analysis showed that tumor cells treated with both CAR T cells and RMC-6236 exhibited a significant upregulation of interferon signaling as compared to either monotherapy alone. STAT1 deletion in PDAC cells abrogated the synergistic tumor cell killing effect.
Conclusions:
In the presence of tumor-specific CAR T cells, pharmacologic RAS inhibition results in a STAT1-dependent increase in interferon signaling in PDAC cells, leading to increased sensitivity to CAR T cell cytotoxicity and improvements in anti-tumor efficacy in vivo. These studies provide a strong rationale for the clinical evaluation of RAS inhibitors in combination with engineered T cells.
Citation Format:
Jayne C. McDevitt, Feiyan Mo, Connor J. Hennessey, William B. Sullivan, Cynthia Clendenin, Il-Kyu Kim, Sydney M. Shaffer, Max M. Wattenberg, Robert H. Vonderheide, Carl H. June, Ben Z. Stanger. Pharmacological RAS inhibition synergizes with CAR T cells for tumor killing [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B104.