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

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

Wehrli, Marc; Guinn, Samantha; Birocchi, Filippo; Kuo, Adam; Sun, Yi; Larson, Rebecca C; Almazan, Antonio J; Scarfò, Irene; Bouffard, Amanda A; Bailey, Stefanie R; Anekal, Praju Vikas; Montero Llopis, Paula; Nieman, Linda T; Song, Yuhui; Xu, Katherine H; Berger, Trisha R; Kann, Michael C; Leick, Mark B; Silva, Harrison; Salas-Benito, Diego; Kienka, Tamina; Grauwet, Korneel; Armstrong, Todd D; Zhang, Rui; Zhu, Qingfeng; Fu, Juan; Schmidts, Andrea; Korell, Felix; Jan, Max; Choi, Bryan D; Liss, And...     »

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.      «

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...     »