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P26. Enhancing efficacy of dual therapy KRAS inhibitor and B7-H3 CAR T cells in preclinical pancreatic ductal adenocarcinoma models

Thursday, March 5, 2026
10:39 AM - 10:46 AM MST
Location: 301D
Introduction: Chimeric antigen receptor (CAR) T cells targeting B7-H3 are an encouraging treatment option in pancreatic ductal adenocarcinoma (PDAC). Yet, their clinical application is hindered by the hostile tumor microenvironment (TME), made of a dense stroma with immunosuppressive cells limiting CAR T cell infiltration and cytotoxicity. Novel KRAS inhibitors provide initial tumor control but fail to deliver long-term survival due to resistance development. However, they promote favorable immunogenic and anti-tumor effects in the TME by increasing T cell infiltration and reducing myeloid-derived suppressor cells. While both are limited as single agent therapies, leveraging the immunomodulatory functions of the KRAS inhibitor can reshape the PDAC TME and enhance CAR T cell function. We evaluated the synergistic effect of B7-H3 CAR T cells and the pan-KRAS inhibitor daraxonrasib (DAR) in preclinical models of PDAC.


Methods:

Patient-derived PDAC9 and cancer-associated fibroblast (CAF) cell lines were used for all experiments. In vitro, PDAC9 and CAF were co-cultured (1:1 ratio) and treated with a combination of DAR and B7-H3 CAR T cells at various effector to target (E:T) ratios. Cell viability was assessed via imaging and metabolic activity assays. In vivo, an immunodeficient, orthotopic PDAC mouse model was treated with 5 million B7-H3 CAR T cells alone, DAR alone (25 mg/kg), or in combination. Tumor size and survival were evaluated.


Results: In vitro the EC50 for PDAC9 was 57 nM. Combination therapy with B7-H3 CAR T cells and DAR was significantly more effective in killing tumor cells than either CAR alone or DAR alone, especially at lower E:T ratios (1:2. 1:4, 1:8) in vitro. The greatest synergistic effect was seen at the 1:8 E:T ratio with cell viability of 32.3% vs. 50.1% in DAR alone (p< 0.007) vs. 78.9% in CAR alone (p< 0.001). Combination therapy with CAR T cells at 1:1 E:T reached the lowest cell viability of 16.3%. In vivo, tumors were significantly smaller at death in the combination group with mean ± SD mm2 of 62.2 ± 23.9 compared to either therapy alone (DAR 109.3 ± 11.7, CAR T 151.6 ± 44.8, control 207.4 ± 55.7, p< 0.001). Survival was significantly longer in the combination and DAR groups (p=0.03). Further subgroup survival and B7-H3 CAR T cell phenotyping and penetration assays are ongoing and expected.


Conclusions: B7-H3 CAR T cells synergize with daraxonrasib in killing PDAC cells and reducing tumor size, with the largest in vitro effect occurring at lower E:T ratios. By leveraging different mechanisms, this combination therapy is highly promising as an effective therapy in PDAC.

Learning Objectives:

  • Learn the parameters of CAR T cell efficiency, efficacy, and interpret these factors in translational experiments
  • Understand the importance of employing different cytotoxic mechanisms against pancreatic tumor cell killing