(1) Wehrli M (2) Guinn S (3) Birocchi F (4) Kuo A (5) Sun Y (6) Larson RC (7) Almazan AJ (8) Scarfò I (9) Bouffard AA (10) Bailey SR (11) Anekal PV (12) Montero Lopis P (13) Nieman LT (14) Song Y (15) Xu KH (16) Berger TR (17) Kann MC (18) Leick MB (19) Silva H (20) Salas-Benito D (21) Kienka T (22) Grauwet K (23) Armstrong TD (24) Zhang R (25) Zhu Q (26) Fu J (27) Schmidts A (28) Korell F (29) Jan M (30) Choi BD (31) Liss AS (32) Boland GM (33) Ting DT (34) Burkhart RA (35) Jenkins RW (36) Zheng L (37) Jaffee EM (38) Zimmerman JW (39) Maus MV

Clinical Cancer Research

Wehrli et al. generated mesothelin CAR T cells secreting a bispecific T cell engager against FAP (mesoFAP T cells) to eliminate both pancreatic cancer cells and immunosuppressive cancer-associated fibroblasts (CAFs). Compared to control CAR T cells, mesoFAP improved both overall tumor control and clearance of FAP+ cells in various CAF-containing models, including a patient-derived xenograft model. Within patient-derived organoids (PDOs) that incorporate endogenous, rapidly-expanding CAFs, mesoFAP promoted robust tumor cell elimination and complete clearance of CAFs, in concert with superior tumor cell-specific lysis and differential activation compared to control CAR T cells.

Contributed by Morgan Janes

PURPOSE: Targeting solid tumors with 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 (CAFs), 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 anti-mesothelin CAR and a secreted T-cell-engaging molecule (TEAM) that targets CAFs 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 CAFs, we examined the ability of mesoFAP CAR-TEAM cells to target PDAC cells and CAFs within the TME. We developed and used patient-derived ex vivo models including patient-derived organoids with patient-matched CAFs and patient-derived organotypic tumor spheroids (PDOTS). RESULTS: We demonstrated specific and significant binding of the TEAM to 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 CAFs compared to T cells engineered to target either antigen alone in our ex-vivo patient-derived 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.

Author Info: (1) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (2) Johns Hopkins University School of Medicine, Baltimore, United States. (3) Massachus

Author Info: (1) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (2) Johns Hopkins University School of Medicine, Baltimore, United States. (3) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (4) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (5) Massachusetts General Hospital, Boston, MA, United States. (6) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (7) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (8) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (9) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (10) University of Virginia, Charlestown, MA, United States. (11) Harvard Medical School, MA, United States. (12) Harvard Medical School, MA, United States. (13) Massachusetts General Hospital Cancer Center, Charlestown, MA, United States. (14) Massachusetts General Hospital Cancer Center, Charlestown, MA, United States. (15) Massachusetts General Hospital, Charlestown, MA, United States. (16) Massachusetts General Hospital, Charlestown, MA, United States. (17) Massachusetts General Hospital, Charlestown, MA, United States. (18) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (19) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (20) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (21) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (22) Massachusetts General Hospital, Boston, Massachusetts, United States. (23) Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, United States. (24) Johns Hopkins University School of Medicine, Baltimore, United States. (25) Johns Hopkins Medicine, Baltimore, MARYLAND, United States. (26) Johns Hopkins University School of Medicine, Baltimore, Maryland, United States. (27) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (28) Massachusetts General Hospital, Charlestown, MA, United States. (29) Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States. (30) Massachusetts General Hospital, Boston, United States. (31) Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States. (32) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (33) Massachusetts General Hospital, Charlestown, MA, United States. (34) Johns Hopkins University, Baltimore, MD, United States. (35) Massachusetts General Hospital, Boston, MA, United States. (36) Johns Hopkins University School of Medicine, Baltimore, Maryland, United States. (37) Johns Hopkins University, Baltimore, MD, United States. (38) Johns Hopkins University, Baltimore, MD, United States. (39) Massachusetts General Hospital, Charlestown, MA, United States.

Citation: Clin Cancer Res 2024 Feb 23 Epub02/23/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38393682

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