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