Zhong et al. demonstrated that CAR T cell-derived TNF activated Rab27a in tumor cells and stimulated the secretion of small extracellular vesicles (sEVs) carrying tumor antigens, including the CAR-targeted antigen, leading to antigen recognition and granzyme B-mediated CAR T cell fratricide. CAR T cells armored with SerpinB9, a granzyme B inhibitor, showed reduced fratricide and increased survival, tumor infiltration, and cytotoxicity in cultures and in solid tumor models. Serpin B9-armored CAR T cells showed higher efficacy than parental CAR T cells when combined with anti-PD-1 in solid tumor models.
Contributed by Shishir Pant
ABSTRACT: The efficacy of chimeric antigen receptor (CAR) T cells against solid tumors is limited. The molecular mechanisms underlying CAR T cell resistance are yet to be elucidated and new strategies need to be developed to improve treatment outcomes. Here we report that solid tumors respond to CAR T cells by upregulating the secretion of small extracellular vesicles carrying tumor antigens, which are horizontally transferred to CAR T cells, leading to antigen recognition and CAR T cell fratricide. Engineered CAR T cells armored with Serpin B9, a major granzyme B inhibitor, show decreased fratricide and increased vitality, tumor infiltration, and antitumor activity in female mice. Moreover, Serpin B9-armored CAR T cells show higher efficacy than parental CAR T cells in treating solid tumors when combined with the anti-programmed death 1 antibody. Our study demonstrates a mechanism that limits CAR T cell function and suggests an improved strategy in tumor treatment.
Author Info: (1) Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Biology, School of Arts and Sciences, University of Pen
Author Info: (1) Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. (3) Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. (4) Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. (5) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (6) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (7) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (8) Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. (9) Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, USA. (10) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (11) Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. (12) Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA. (13) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (14) Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. guowei@sas.upenn.edu.
