Journal
NATURE
Volume 568, Issue 7750, Pages 112-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41586-019-1054-1
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Funding
- Lake Road Foundation
- Lymphoma and Leukaemia Society
- NCI Cancer Center Support Grant [P30 CA008748]
- Tow Foundation
- Cycle for Survival
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
- NCI grant [P30 CA08748]
- Canadian Institutes of Health Research
- Alexander S. Onassis Public Benefit Foundation
- Pasteur-Weizmann/Servier award
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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.
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