Science Highlights
Published on January 13, 2026
Using ibrutinib and PD-1 blockade to enhance mesothelin-targeted CAR T-cell therapy in PDAC
by Clinical Cancer Research
Armstrong A, van der Plancke G, Nishiguchi S, et al. Ibrutinib and PD-1 Blockade Potentiate Mesothelin-Targeting CAR-T Cell Therapy in Preclinical Models of Pancreatic Cancer. Clinical Cancer Research. 2025; (doi: 10.1158/1078-0432.CCR-25-2907).
Chimeric antigen receptor (CAR) T-cell treatment has had limited success against pancreatic ductal adenocarcinoma (PDAC), but there is hope that incorporating ibrutinib or PD-1 blockade might reverse the trend. PDAC is challenging due to its immunosuppressive microenvironment, characterized by tumor mesothelin shedding, and because of cancer-associated fibroblast (CAF) activity, which hinders CAR T-cell infiltration. Mesothelin-specific CAR T cells, paired with a T-cell engager antibody molecule (TEAM), have demonstrated the capacity to kill tumor cells and CAF. Now, researchers have matched mesothelin-specific CAR T cells with different drug combinations, testing them in preclinical PDAC models. Pharmacologic options were selected based on their potential to amplify tumor mesothelin expression or support T-cell function, with ibrutinib and PD-1 blockade emerging as the top candidates. Ibrutinib improved CAR T-cell expansion, Th1 skewing, and antitumor activity in PDAC, while PD-1 blockade improved CAR T-cell antitumor function in a patient-derived PDAC xenograft. To further explore their potential to optimize CAR T-cell therapy against PDAC, a planned Phase I study will compare outcomes using the previously developed CAR-TEAM construct alone and in combination with ibrutinib or PD-1 blockade.
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