Ibrutinib and PD-1 Blockade Potentiate Mesothelin-Targeting CAR T-cell Therapy in Preclinical Models of Pancreatic Cancer.

Abstract

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. 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. 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. 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.