Ibrutinib and PD-1 blockade potentiate mesothelin-targeting CAR-T cell therapy in preclinical models of pancreatic cancer

  • Clin Cancer Res. 2025 Nov 13:10.1158/1078-0432.CCR-25-2907. doi: 10.1158/1078-0432.CCR-25-2907.
Alexander Armstrong  1 ,  Graziella van der Plancke  2 ,  Sae Nishiguchi  3 ,  Diego Salas-Benito  4 ,  Amanda A Bouffard  1 ,  Sadie Goncalves  1 ,  Ashlyn T Merce  5 ,  Christopher Kelly  6 ,  Filippo Birocchi  4 ,  Sangwoo Park  7 ,  Mark B Leick  1 ,  Nora Horick  2 ,  Trisha R Berger  8 ,  Marcela V Maus  8 ,  Giulia Escobar  1
Affiliations
  • 1. Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States.
  • 2. Massachusetts General Hospital, Boston, MA, United States.
  • 3. Massachusetts General Hospital Cancer Center, United States.
  • 4. Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States.
  • 5. Massachusetts General Hospital, Charlestown, Massachusetts, United States.
  • 6. Mass General Brigham, United States.
  • 7. Massachusetts General Hospital, United States.
  • 8. Massachusetts General Hospital, Charlestown, MA, United States.
PMID: 41231131 DOI: 10.1158/1078-0432.CCR-25-2907
Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains refractory to chimeric antigen receptor (CAR) T cell therapies due to its immunosuppressive microenvironment and a dense extracellular matrix deposited by cancer-associated fibroblasts (CAFs), 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 FAP-targeting T cell engager antibody molecule (TEAM) to simultaneously kill tumor cells and CAFs. Here, 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 pre-clinical 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 anti-tumor activity in PDAC. PD-1 blockade synergistically improved CAR-T cell anti-tumor function in a patient-derived PDAC xenograft and intraperitoneal delivery proved superior against peritoneal disease. Conversely, while an ADAM10/17 inhibitor prevented Mesothelin shedding and improved tumor killing in vitro, it did not enhance efficacy in vivo.

Conclusion: 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.

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