Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
Ibrutinib and PD-1 Blockade Potentiate Mesothelin-Targeting CAR T-cell Therapy in Preclinical Models of Pancreatic Cancer.
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Armstrong Alexander, van der Plancke Graziella, Nishiguchi Sae, Salas-Benito Diego, Bouffard Amanda A, Goncalves Sadie, Merce Ashlyn T, Kelly Christopher, Birocchi Filippo, Park Sangwoo, Leick Mark B, Horick Nora, Berger Trisha R, Maus Marcela V, Escobar Giulia
Аннотация
PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) remains refractory to chimeric antigen receptor (CAR) T-cell therapies because of its immunosuppressive microenvironment and a dense extracellular matrix deposited by cancer-associated fibroblasts (CAF), which impair CAR T-cell infiltration. To address these barriers, we previously developed a dual-targeting CAR-TEAM platform in which mesothelin-specific CAR T cells secrete a fibroblast activation protein (FAP)-targeting T-cell engager antibody molecule (TEAM) to simultaneously kill tumor cells and CAF. In this study, we leveraged mesothelin-targeting CAR T cells and tested rational drug combinations and optimal delivery strategies to enhance therapeutic efficacy and guide potential combinations that could be incorporated into a clinical study.
EXPERIMENTAL DESIGN: Tumor mesothelin shedding by proteases and CAR T-cell dysfunction remain key obstacles to CAR T-cell efficacy. Using preclinical PDAC models, we tested mesothelin-targeting CAR T cells in combination with agents that increase tumor mesothelin expression, promote T-cell polarization and persistence, and support T-cell function. Furthermore, we compared intravenous versus intraperitoneal delivery routes to treat peritoneal metastases.
RESULTS: We demonstrated that ibrutinib enhanced CAR T-cell expansion, Th1 skewing, and antitumor activity in PDAC. PD-1 blockade synergistically improved CAR T-cell antitumor function in a patient-derived PDAC xenograft and intraperitoneal delivery proved superior against peritoneal disease. Conversely, although an ADAM-10/-17 inhibitor prevented mesothelin shedding and improved tumor killing in vitro, it did not enhance efficacy in vivo.
CONCLUSIONS: These findings identify clinically actionable strategies to optimize CAR T-cell therapy against PDAC. A phase I clinical trial testing meso-FAP CAR-TEAM T cells, alone or in combination with ibrutinib or PD-1 blockade, is in development.
EXPERIMENTAL DESIGN: Tumor mesothelin shedding by proteases and CAR T-cell dysfunction remain key obstacles to CAR T-cell efficacy. Using preclinical PDAC models, we tested mesothelin-targeting CAR T cells in combination with agents that increase tumor mesothelin expression, promote T-cell polarization and persistence, and support T-cell function. Furthermore, we compared intravenous versus intraperitoneal delivery routes to treat peritoneal metastases.
RESULTS: We demonstrated that ibrutinib enhanced CAR T-cell expansion, Th1 skewing, and antitumor activity in PDAC. PD-1 blockade synergistically improved CAR T-cell antitumor function in a patient-derived PDAC xenograft and intraperitoneal delivery proved superior against peritoneal disease. Conversely, although an ADAM-10/-17 inhibitor prevented mesothelin shedding and improved tumor killing in vitro, it did not enhance efficacy in vivo.
CONCLUSIONS: These findings identify clinically actionable strategies to optimize CAR T-cell therapy against PDAC. A phase I clinical trial testing meso-FAP CAR-TEAM T cells, alone or in combination with ibrutinib or PD-1 blockade, is in development.