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

Autor:	Wehrli M; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Guinn S; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.; Cancer Convergence Institute and Bloomberg Kimmel Institute at Johns Hopkins, University, Baltimore, Maryland., Birocchi F; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Kuo A; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Sun Y; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Larson RC; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Almazan AJ; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Scarfò I; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Bouffard AA; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Bailey SR; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Anekal PV; MicRoN Core, Harvard Medical School, Boston, Massachusetts., Montero Llopis P; MicRoN Core, Harvard Medical School, Boston, Massachusetts., Nieman LT; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Song Y; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Xu KH; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Berger TR; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Kann MC; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Leick MB; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Blood and Marrow Transplant Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Silva H; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Salas-Benito D; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Kienka T; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Grauwet K; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Armstrong TD; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.; Cancer Convergence Institute and Bloomberg Kimmel Institute at Johns Hopkins, University, Baltimore, Maryland., Zhang R; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.; Cancer Convergence Institute and Bloomberg Kimmel Institute at Johns Hopkins, University, Baltimore, Maryland., Zhu Q; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.; Cancer Convergence Institute and Bloomberg Kimmel Institute at Johns Hopkins, University, Baltimore, Maryland., Fu J; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.; Cancer Convergence Institute and Bloomberg Kimmel Institute at Johns Hopkins, University, Baltimore, Maryland., Schmidts A; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Korell F; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Jan M; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Choi BD; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Liss AS; Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Boland GM; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Ting DT; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Burkhart RA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.; Cancer Convergence Institute and Bloomberg Kimmel Institute at Johns Hopkins, University, Baltimore, Maryland., Jenkins RW; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Zheng L; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.; Cancer Convergence Institute and Bloomberg Kimmel Institute at Johns Hopkins, University, Baltimore, Maryland., Jaffee EM; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.; Cancer Convergence Institute and Bloomberg Kimmel Institute at Johns Hopkins, University, Baltimore, Maryland., Zimmerman JW; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.; Cancer Convergence Institute and Bloomberg Kimmel Institute at Johns Hopkins, University, Baltimore, Maryland., Maus MV; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.; Blood and Marrow Transplant Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 May 01; Vol. 30 (9), pp. 1859-1877.
DOI:	10.1158/1078-0432.CCR-23-3841
Abstrakt:	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 patient-derived 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 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 CAF compared with 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. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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