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Driving CAR T-cells forward

Key Points

  • Chimeric antigen receptor (CAR)-T-cell therapy has shown enormous promise in the treatment of B-cell acute lymphoblastic leukaemia; at present, CD19-targeted CAR-T-cell-based treatment of other B-cell malignancies is less effective

  • Other targets for CAR-T-cell therapy of haematological malignancies that are undergoing clinical testing include CD20, CD22, ROR1, IgΚ, BCMA, CD138, CD33, CD123 and LewisY antigen

  • Targets for CAR-T-cell therapy of solid malignancies currently being tested in the clinic include PSMA, FAP, CEA, CD171, GD2, glypican-3, HER2 and IL-13Rα

  • Several strategies are under development to improve CAR-T-cell-mediated antitumour responses; these include, among others, 'armoured' CAR T cells, dual receptor/cytokine-based CARs, CARs based on natural-killer-cell receptors and other cell receptors

  • Strategies to improve the safety of CAR-T-cell therapy involve improved management of cytokine-release syndrome, as well as engineered CAR T cells that are easier to eradicate in case of adverse events

Abstract

The engineered expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. Early clinical trials using CAR T cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm for this approach. Important lessons have been derived from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in haematological and solid malignancies. In this Review, we discuss these trials and present strategies that can increase the antitumour efficacy and safety of CAR T-cell therapy. Given the fast-moving nature of this field, we only discuss studies with direct translational application currently or soon-to-be tested in the clinical setting.

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Figure 1: CAR-T-cell design.
Figure 2: Approaches to improve CAR-T-cell therapy.

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Acknowledgements

R.J.B. receives financial support from The Annual Terry Fox Run for Cancer Research (New York) organized by the Canada Club of New York, Carson Family Charitable Trust, Kate's Team, Emerald Foundation, the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center (Innovations in the structures, functions and targets of monoclonal antibody-based drugs for cancer), The Leukemia & Lymphoma society, The National Institutes of Health Grants (R01CA138738-05, PO1CA059350, PO1CA190174-01) and the William Lawrence and Blanche Hughes Foundation.

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H.J.J., S.R. and R.J.B. researched data for the article, contributed to discussing the article's content, wrote, reviewed and edited the manuscript before submission.

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Correspondence to Renier J. Brentjens.

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H.J.J. and S.R. declare no competing interests. R.J.B. is a co-founder, stockholder and consultant for Juno Therapeutics Inc.

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Jackson, H., Rafiq, S. & Brentjens, R. Driving CAR T-cells forward. Nat Rev Clin Oncol 13, 370–383 (2016). https://doi.org/10.1038/nrclinonc.2016.36

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