Hamieh et al. demonstrated in several leukemia mouse models that CAR T cells acquire the target antigen from tumor cells via trogocytosis, leading to tumor relapse due to resistance to killing at low tumor antigen density, fratricide of the CAR T cells which acquired antigen, and exhaustion of antigen-negative CAR T cells. Trogocytosis was observed across multiple targets, and for CD19 it was associated with diminished CAR expression. The sensitivity of CAR T cells to antigen loss depended on their costimulatory domain and could be overcome by a higher effector:target ratio (inducing cooperativity between CAR T cells) or simultaneous targeting of multiple antigens.
Chimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence(1). Patient-derived CAR T cells have demonstrated remarkable efficacy against a range of B-cell malignancies(1-3), and the results of early clinical trials suggest activity in multiple myeloma(4). Despite high complete response rates, relapses occur in a large fraction of patients; some of these are antigen-negative and others are antigen-low(1,2,4-9). Unlike the mechanisms that result in complete and permanent antigen loss(6,8,9), those that lead to escape of antigen-low tumours remain unclear. Here, using mouse models of leukaemia, we show that CARs provoke reversible antigen loss through trogocytosis, an active process in which the target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide T cell killing and T cell exhaustion. These mechanisms affect both CD28- and 4-1BB-based CARs, albeit differentially, depending on antigen density. These dynamic features can be offset by cooperative killing and combinatorial targeting to augment tumour responses to immunotherapy.
Author Info: (1) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, U
Author Info: (1) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Immunology Program, Sloan Kettering Institute, New York, NY, USA. (10) Microchemistry and Proteomics Core Laboratory, Sloan Kettering Institute, New York, NY, USA. (11) Microchemistry and Proteomics Core Laboratory, Sloan Kettering Institute, New York, NY, USA. (12) Quantitative Sciences Unit, Stanford University School of Medicine, Palo Alto, CA, USA. (13) Immunology Program, Sloan Kettering Institute, New York, NY, USA. (14) Microchemistry and Proteomics Core Laboratory, Sloan Kettering Institute, New York, NY, USA. Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY, USA. (15) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY, USA. (16) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY, USA. (17) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. m-sadelain@ski.mskcc.org. Immunology Program, Sloan Kettering Institute, New York, NY, USA. m-sadelain@ski.mskcc.org.
