Abstract PR010: A mutant KRAS-targeted peptide vaccine in combination with RAS(ON) multi-selective inhibition and immune checkpoint modulators enhances anti-tumor immunity in preclinical PDAC models
Zirui Zhu, Benjamin Barrett, Aadi Bhattacharya, Hejia Wang, Kylie Belanger, Tessa Seale, Yue Pan, Amanda Huff, Todd Armstrong, James Leatherman, Jacquelyn Zimmerman, Nilofer Azad, Elizabeth Jaffee, Sandra Misale, Eric Christenson, Neeha ZaidiAbstract
Background:
Recent clinical advances using RAS-targeted small-molecule inhibitors, including daraxonrasib, a RAS(ON) multi-selective, noncovalent, tri-complex inhibitor, has shown promising responses but are limited in durability for pancreatic ductal adenocarcinoma (PDAC). Preclinical studies indicate that RAS inhibition can reprogram the immunosuppressive PDAC tumor microenvironment (TME). To further leverage the immunomodulatory effects of RAS inhibitors, particularly in immune-resistant contexts, we evaluated mutant KRAS vaccine (mKRAS Vax), a synthetic long peptide vaccine developed by our group, that targets the six most common KRAS mutations in PDAC, in combination with immune checkpoint modulators (ICMs) to enhance and prolong responses to RAS inhibition.
Methods:
Syngeneic PDAC murine models, KPCY 2838c3 (c3) and 6419c5 (c5), characterized by relatively T cell-high and T cell-low TMEs, respectively, were used to assess the anti-tumor activity of combination treatments. mKRAS-specific T cell responses were determined using ELISpot assays. Flow cytometry was used to evaluate treatment-induced changes in the tumor-infiltrating immune cell populations.
Results:
RMC-7977, a preclinical tool compound representative of the investigational agent daraxonrasib, exhibited tumor-intrinsic effects on upregulating IFNγ and MHC expressions in vitro in both KPCY models. In the c3 model, RMC-7977 enhanced vaccine-induced mKRAS-specific T cell infiltration into tumors, and mKRAS Vax improved the depth of response to RAS inhibition. mKRAS Vax elicited predominantly mKRAS-specific CD4+ T cell responses, which are essential for the effector function of CD8+ T cells in the c3 model. Moreover, the addition of mKRAS Vax augmented the response to RMC-7977 plus anti-PD-1 treatment and delayed tumor regrowth after treatment cessation. This triple combination promoted robust T cell recruitment, with reduced Treg abundance, increased Th1 polarization, and cytotoxic CD8+ T cells. In the T cell-low c5 model, RMC-7977 with ICM combinations had minimal synergistic effects, but inclusion of mKRAS Vax significantly slowed disease progression. In both subcutaneous and orthotopic c5 models, incorporation of anti-CTLA4 during the priming phase and 4-1BB agonist achieved the most robust and durable responses when combined with mKRAS Vax and RMC-7977. mKRAS Vax and 4-1BB agonist predominantly induced CD8+ T cell proliferation and memory phenotypes in the TME and tumor-draining lymph nodes.
Conclusions:
mKRAS Vax enhanced both depth and durability of the response when combined with a RAS(ON) multi-selective inhibitor and ICMs therapy in T cell-high and T cell-low PDAC models by promoting a more robust anti-tumor TME modulation, accompanied by an increase in mKRAS-reactive T cell recruitment. Together, these preclinical findings provide novel insights into the optimal strategies for integrating RAS(ON) inhibitors with immune-directed therapies and highlight the potential of mKRAS Vax to potentiate anti-tumor immunity in immune-refractory settings.
Citation Format:
Zirui Zhu, Benjamin Barrett, Aadi Bhattacharya, Hejia Wang, Kylie Belanger, Tessa Seale, Yue Pan, Amanda Huff, Todd Armstrong, James Leatherman, Jacquelyn Zimmerman, Nilofer Azad, Elizabeth Jaffee, Sandra Misale, Eric Christenson, Neeha Zaidi. A mutant KRAS-targeted peptide vaccine in combination with RAS(ON) multi-selective inhibition and immune checkpoint modulators enhances anti-tumor immunity in preclinical PDAC models [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 PR010.