Editors' ChoiceImmunotherapy

Fast and furious: Why all CARs are not made equal

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Science Translational Medicine  27 May 2015:
Vol. 7, Issue 289, pp. 289ec86
DOI: 10.1126/scitranslmed.aac5086

Engineered T lymphocytes that express chimeric antibodies, which target tumor antigens, have recently shown impressive clinical activity in aggressive B-cell malignancies. However, despite early promising results, adoptive chimeric antigen receptor (CAR) T cell therapy has seen limited progress for solid tumors; the mechanisms behind this failure are not clearly understood.

Long et al. provide a potential explanation to the limited success of CAR immunotherapy to targets other than CD19. The CAR T cells tested, with the exception of the highly effective CD19 CAR, retained cytolytic capacity in vitro but showed limited expansion, persistence, and antitumor efficacy in in vivo xenograft mouse models. The phenotypic, functional, and transcriptional characteristics of these CARs demonstrated that they become rapidly exhausted through antigen-independent tonic signaling, perhaps from physical interactions between CAR receptors that self-associated on the cell surface. Further, the authors were able to mitigate these effects by incorporating the 4-1BB endodomain instead of CD28, which increased persistence of these T cells in vivo, decreased expression of exhaustion markers such as PD-1, and increased antitumor activity. Gene set enrichment analysis demonstrated that 4-1BB ameliorated exhaustion in part by diminishing expression of exhaustion-related genes, and also by modulating T cell apoptosis.

The realization that CAR endodomains can drive T cell exhaustion in addition to tumor-induced immunosuppressive effects highlights the importance of optimizing CAR T cell engineering. Next generation CARs may effectively eliminate the issue of T cell exhaustion and ensure adequate survival and persistence of CAR cells in the months following initial therapy.

A. H. Long et al., 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. 10.1038/nm.3838 (2015). [Abstract]

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