Review Article | Published:

Mechanisms of resistance to CAR T cell therapy

Nature Reviews Clinical Oncology (2019) | Download Citation

Abstract

The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B cell lymphomas have revolutionized anticancer therapy, providing a potentially curative option for patients who are refractory to standard treatments. These trials resulted in rapid FDA approvals of anti-CD19 CAR T cell products for both ALL and certain types of B cell lymphoma — the first approved gene therapies in the USA. However, growing experience with these agents has revealed that remissions will be brief in a substantial number of patients owing to poor CAR T cell persistence and/or cancer cell resistance resulting from antigen loss or modulation. Furthermore, the initial experience with CAR T cells has highlighted challenges associated with manufacturing a patient-specific therapy. Understanding the limitations of CAR T cell therapy will be critical to realizing the full potential of this novel treatment approach. Herein, we discuss the factors that can preclude durable remissions following CAR T cell therapy, with a primary focus on the resistance mechanisms that underlie disease relapse. We also provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms.

Key points

  • Chimeric antigen receptor (CAR) T cell immunotherapy is a highly effective form of adoptive cell therapy, as demonstrated by the remission rates in patients with B cell acute lymphoblastic leukaemia or large B cell lymphoma, which have supported FDA approvals.

  • A complete understanding of the limitations of CAR T cell therapy will help to identify crucial areas requiring further research to improve patient outcomes.

  • Factors that can preclude durable remissions following CAR T cell therapy include CAR T cell manufacturing issues, limited CAR T cell expansion and/or persistence, various resistance mechanisms and toxicities.

  • Various intuitive strategies to overcome these obstacles are being investigated in order to optimize this unique therapeutic strategy and expand the indications for treatment.

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Acknowledgements

The work of the authors is supported in part by the Intramural Research Program, the National Cancer Institute and the NIH Clinical Center.

Reviewer information

Nature Reviews Clinical Oncology thanks S. Grupp and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Affiliations

  1. Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    • Nirali N. Shah
  2. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    • Terry J. Fry
  3. Center for Cancer and Blood Disorders, Children’s Hospital Colorado, Aurora, CO, USA

    • Terry J. Fry

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Both authors made substantial contributions to all stages of the preparation of this manuscript.

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The authors declare no competing interests.

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Correspondence to Nirali N. Shah.

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https://doi.org/10.1038/s41571-019-0184-6