Mesothelin CAR T Cells Secreting Anti-FAP/Anti-CD3 Molecules Efficiently Target Pancreatic Adenocarcinoma and its Stroma

Marc Wehrli, Samantha Guinn, Filippo Birocchi, Adam Kuo, Yi Sun, Rebecca C. Larson, Antonio J. Almazan, Irene Scarfó, Amanda A. Bouffard, Stefanie R. Bailey, Praju Vikas Anekal, Paula Montero Llopis, Linda T. Nieman, Yuhui Song, Katherine H. Xu, Trisha R. Berger, Michael C. Kann, Mark B. Leick, Harrison Silva, Diego Salas-BenitoTamina Kienka, Korneel Grauwet, Todd D. Armstrong, Rui Zhang, Qingfeng Zhu, Juan Fu, Andrea Schmidts, Felix Korell, Max Jan, Bryan D. Choi, Andrew S. Liss, Genevieve M. Boland, David T. Ting, Richard A. Burkhart, Russell W. Jenkins, Lei Zheng, Elizabeth M. Jaffee, Jackie Zimmerman, Marcela V. Maus

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Targeting solid tumors with chimeric antigen receptor (CAR) T cells remains challenging due to heterogenous target antigen expression, antigen escape, and the immunosuppressive tumor microenvironment (TME). Pancreatic cancer is characterized by a thick stroma generated by cancer-associated fibroblasts (CAF), which may contribute to the limited efficacy of mesothelin-directed CAR T cells in early-phase clinical trials. To provide a more favorable TME for CAR T cells to target pancreatic ductal adenocarcinoma (PDAC), we generated T cells with an antimesothelin CAR and a secreted T-cell-engaging molecule (TEAM) that targets CAF through fibroblast activation protein (FAP) and engages T cells through CD3 (termed mesoFAP CAR-TEAM cells). Experimental Design: Using a suite of in vitro, in vivo, and ex vivo patient-derived models containing cancer cells and CAF, we examined the ability of mesoFAP CAR-TEAM cells to target PDAC cells and CAF within the TME. We developed and used patientderived ex vivo models, including patient-derived organoids with patient-matched CAF and patient-derived organotypic tumor spheroids. Results: We demonstrated specific and significant binding of the TEAMto its respective antigens (CD3 and FAP) when released from mesothelin-targeting CAR T cells, leading to T-cell activation and cytotoxicity of the target cell. MesoFAP CAR-TEAM cells were superior in eliminating PDAC and CAF compared with T cells engineered to target either antigen alone in our ex vivo patientderived models and in mouse models of PDAC with primary or metastatic liver tumors. Conclusions: CAR-TEAM cells enable modification of tumor stroma, leading to increased elimination of PDAC tumors. This approach represents a promising treatment option for pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)1859-1877
Number of pages19
JournalClinical Cancer Research
Volume30
Issue number9
DOIs
StatePublished - May 1 2024

ASJC Scopus subject areas

  • General Medicine

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