Mohamad Hamieh, Anton Dobrin, Annalisa Cabriolu, Sjoukje J C van der Stegen, Theodoros Giavridis, Jorge Mansilla-Soto, Justin Eyquem, Zeguo Zhao, Benjamin M Whitlock, Matthew M Miele, Zhuoning Li, Kristen M Cunanan, Morgan Huse, Ronald C Hendrickson, Xiuyan Wang, Isabelle Rivière, Michel Sadelain
Nature 2019 AprChimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence1. Patient-derived CAR T cells have demonstrated remarkable efficacy against a range of B-cell malignancies1-3, and the results of early clinical trials suggest activity in multiple myeloma4. Despite high complete response rates, relapses occur in a large fraction of patients; some of these are antigen-negative and others are antigen-low1,2,4-9. Unlike the mechanisms that result in complete and permanent antigen loss6,8,9, 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.
Mohamad Hamieh, Anton Dobrin, Annalisa Cabriolu, Sjoukje J C van der Stegen, Theodoros Giavridis, Jorge Mansilla-Soto, Justin Eyquem, Zeguo Zhao, Benjamin M Whitlock, Matthew M Miele, Zhuoning Li, Kristen M Cunanan, Morgan Huse, Ronald C Hendrickson, Xiuyan Wang, Isabelle Rivière, Michel Sadelain. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature. 2019 Apr;568(7750):112-116
PMID: 30918399
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