CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape

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 and Michel Sadelain ()
Additional contact information
Mohamad Hamieh: Memorial Sloan Kettering Cancer Center
Anton Dobrin: Memorial Sloan Kettering Cancer Center
Annalisa Cabriolu: Memorial Sloan Kettering Cancer Center
Sjoukje J. C. van der Stegen: Memorial Sloan Kettering Cancer Center
Theodoros Giavridis: Memorial Sloan Kettering Cancer Center
Jorge Mansilla-Soto: Memorial Sloan Kettering Cancer Center
Justin Eyquem: Memorial Sloan Kettering Cancer Center
Zeguo Zhao: Memorial Sloan Kettering Cancer Center
Benjamin M. Whitlock: Sloan Kettering Institute
Matthew M. Miele: Sloan Kettering Institute
Zhuoning Li: Sloan Kettering Institute
Kristen M. Cunanan: Stanford University School of Medicine
Morgan Huse: Sloan Kettering Institute
Ronald C. Hendrickson: Sloan Kettering Institute
Xiuyan Wang: Memorial Sloan Kettering Cancer Center
Isabelle Rivière: Memorial Sloan Kettering Cancer Center
Michel Sadelain: Memorial Sloan Kettering Cancer Center

Nature, 2019, vol. 568, issue 7750, 112-116

Abstract: Abstract Chimeric 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.

Date: 2019
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DOI: 10.1038/s41586-019-1054-1

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