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CANCER IMMUNOTHERAPY IN 2018

CAR T cell therapy: inroads to response and resistance

  • Year in Review
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From Nature Reviews Immunology

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Here, we highlight key papers published in 2018 that advance our understanding of resistance to chimeric antigen receptor (CAR) T cell immunotherapy for leukaemia and lymphoma and in so doing reveal barriers that must be addressed to increase efficacy of this novel class of therapeutics for B cell malignancies and expand their reach to solid tumours.

Key advances

  • CD19-targeted chimeric antigen receptor (CAR) T cells induce high complete response rates in paediatric B cell acute lymphoblastic leukaemia (B-ALL) cases, but many of these patients will relapse, most often with CD19-negative leukaemia.

  • CD22-directed CAR T cells induce high response rates in CD19-naive or CD19-resistant B-ALL, but often relapse with CD22lo leukaemia.

  • Intrinsic gene programmes of memory versus exhaustion correlate with T cell fitness and determine response to CD19-targeted CAR T cells in chronic lymphocytic leukaemia (CLL).

  • Loss of Tet methylcytosine dioxygenase 2 (TET2), an epigenetic modulator, prevented terminal T cell differentiation and enabled the progeny of a single CD8+ CAR T cell clone to mediate complete remission in a patient with CLL.

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Fig. 1: Major mechanisms of acquired resistance to CAR T cells.

References

  1. Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

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Acknowledgements

C.L.M. and C.B. are members of the Parker Institute for Cancer Immunotherapy, which supports the Stanford University and City of Hope Cancer Immunotherapy Program.

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Authors and Affiliations

  1. Heritage Provider Network Professor in Immunotherapy, City of Hope, Duarte, CA, USA

    Christine E. Brown

  2. Ernest and Amelia Gallo Family Professor of Pediatrics and Medicine, Stanford University, Stanford, CA, USA

    Crystal L. Mackall

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  1. Christine E. Brown
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  2. Crystal L. Mackall
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Correspondence to Crystal L. Mackall.

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Competing interests

C.L.M. is a member of the Scientific Advisory board and/or has provided consulting services for Adaptimmune LLC, Allogene, Apricity Health, GlaxoSmithKline Cell and Gene Therapy, Lyell Immunopharma, Nektar, PACT Pharma, Pfizer, Roche, TPG, Unum Therapeutics and Vor Pharmaceuticals. C.L.M. owns equity in Apricity Health, Lyell Immunopharma, PACT Pharma, Unum Therapeutics and Vor Pharmaceuticals and has received research funding from Bluebird Bio and Obsidian Therapeutics. C.B. declares no competing interests.

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Brown, C.E., Mackall, C.L. CAR T cell therapy: inroads to response and resistance. Nat Rev Immunol 19, 73–74 (2019). https://doi.org/10.1038/s41577-018-0119-y

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