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Investigating ibrutinib and PD-1 inhibition to enhance mesothelin-targeted CAR cell therapy

Armstrong A, van der Plancke G, Nishiguchi S 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).

After developing a chimeric antigen receptor (CAR) construct to address features of pancreatic ductal adenocarcinoma (PDAC) that resist CAR T-cell treatment, researchers explored actionable strategies for advancing the intervention toward clinical discovery. Their experimental platform employs mesothelin-directed CAR T cells, meant to counter tumor mesothelin shedding that erodes CAR T-cell efficacy. The mesothelin-specific cells secrete a T-cell engager antibody molecule (TEAM) that targets fibroblast activation protein (FAP), thus destroying cancer-associated fibroblasts — which hinder CAR T-cell infiltration — along with tumor cells. To further refine the therapy, the team used preclinical models of PDAC to identify promising drug combinations, with a focus on agents known to boost tumor mesothelin expression, promote T-cell function, and foster T-cell polarization and persistence. Ibrutinib emerged as a strong candidate based on improved CAR T-cell expansion, Th1 skewing, and antitumor activity in PDAC. Also promising was PD-1 blockade, which enhanced CAR T-cell antitumor function in a patient-derived PDAC xenograft model. A Phase I study to evaluate meso-FAP CAR-TEAM T cells, alone or in combination with ibrutinib or PD-1 blockade, is now being planned.

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