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  • Review Article
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Chimeric antigen receptor T-cell therapy — assessment and management of toxicities

Nature Reviews Clinical Oncology volume 15, pages 47–62 (2018)Cite this article

Subjects

Key Points

  • Chimeric antigen receptor (CAR)-T-cell therapy is a promising approach for the treatment of refractory malignancies, but is associated with unique acute toxicities that need specialized monitoring and management

  • Cytokine-release syndrome (CRS) and CAR-T-cell-related encephalopathy syndrome (CRES) are the most-common toxicities observed after CAR-T-cell therapy and, rarely, CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH)

  • Intensive monitoring, accurate grading, and prompt management of toxicities with aggressive supportive care, anti-IL-6 therapy, and/or corticosteroids for severe cases could reduce the morbidity and mortality associated with CAR-T-cell therapy

  • The guidelines proposed could also be used for grading and management of toxicities associated with other redirected-T-cell therapies, such as TCR-gene therapies and bispecific T-cell-engaging antibody (BiTE) therapies

Abstract

Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.

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Figure 1: Clinical case study.
Figure 2: Three-step approach to the assessment and management of acute toxicities associated with chimeric antigen receptor (CAR)-T-cell therapy.
Figure 3: Recommendations for the management of Chimeric antigen receptor (CAR)-T-cell-related haemophagocytic lymphohistiocytosis/macrophage-<>activation syndrome (HLH/MAS).

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Acknowledgements

The work of S.S.N. is supported by The University of Texas MD Anderson Cancer Center Support Grant (P30 CA016672) from the US Department of Health & Human Services, National Institutes of Health, and by generous philanthropic contributions to the University of Texas MD Anderson Moon Shots Program.

Author information

Authors and Affiliations

  1. Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Sattva S. Neelapu, Jason Westin & Sherry Adkins

  2. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Sudhakar Tummala, Monica E. Loghin & John F. de Groot

  3. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Partow Kebriaei, Katayoun Rezvani & Elizabeth J. Shpall

  4. Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    William Wierda, Nitin Jain & Naval Daver

  5. Department of Critical Care, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Cristina Gutierrez

  6. Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, 33613, Florida, USA

    Frederick L. Locke

  7. Adult Stem Cell Transplant Program, Sylvester Comprehensive Cancer Center, University of Miami, 1475 Northwest 12 th Avenue, Miami, 33136, Florida, USA

    Krishna V. Komanduri

  8. Division of Hematology, Mayo Clinic, 200 First Street South West, Rochester, 55905, Minnesota, USA

    Yi Lin

  9. Division of Pharmacy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Alison M. Gulbis

  10. Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, Texas, USA

    Suzanne E. Davis & Patrick Hwu

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Contributions

S.S.N. and S.T. contributed equally to this article, and wrote the manuscript. S.S.N., S.T., N.J., N.D., A.M.G., and S.A. contributed to researching data for article. All authors contributed to discussions of content, to the development of the proposed guidelines, and to review/editing of the manuscript before submission.

Corresponding author

Correspondence to Sattva S. Neelapu.

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Competing interests

S.S.N. has received research support from Bristol-Myers Squibb, Celgene, Cellectis, Kite Pharma, Merck, and Poseida Therapeutics. S.S.N. has also served as a consultant and/or Scientific Advisory Board member for Celgene, Kite Pharma, Merck, and Novartis. S.T. served as a Scientific Advisory Board member for Kite Pharma. F.L.L. has served as a Scientific Advisory Board member for Kite Pharma, and as a Consultant to Cellular Biomedicine Group. K.V.K. has served as a scientific advisor to and has received research funding from Juno Therapeutics and Kite Pharma. Y.L. has received research funding from Janssen. N.J. has received research support from Abbvie, ADC Therapeutics, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Pharmacyclics, Pfizer, Seattle Genetics, Servier, and Verastem. N.J. has also served on the advisory board and received honorarium from Adaptive Biotechnologies, ADC Therapeutics, Novartis, Novimmune, Pharmacyclics, Pfizer, Servier, and Verastem. N.D. has received research support from Bristol-Myers Squibb, Daichi-Sanky, Incyte, Karyopharm, Pfizer, and Sunesis. N.D. has also received served as a consultant for Incyte, Jazz, Karyopharm, Novartis, Otsuka, Pfizer, and Sunesis. J.W. has received research funding and served on the Advisory Boards for Kite Pharma and Novartis. J.F.d.G. has received research support from Astrazeneca, Deciphera Pharmaceuticals, Eli Lilly, EMD-Serono, Mundipharma, Novartis, Sanofi-Aventis. J.F.d.G. has also served as a consultant or Advisory Board member for AbbVie, Astrazeneca, Celldex, Deciphera Pharmaceuticals, FivePrime Therapeutics, Foundation Medicine, Genentech, Insys Therapeutics, Kadmon, Merck, Novartis, and Novogen. J.F.d.G. is a stock owner of Gilead and Ziopharm Oncology, and his spouse is employed by Ziopharm Oncology. S.A. served as an Advisory Board member for Kite Pharma. K.R. is on the Independent Data Monitoring Committee for Kiadis Pharma. The other authors declare no competing interests.

Supplementary information

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Comparison of tocilizumab and siltuximab (PDF 128 kb)

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Example customized tracking tool for toxicities of CAR-T-cell therapy in EHRs (PDF 151 kb)

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Neelapu, S., Tummala, S., Kebriaei, P. et al. Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nat Rev Clin Oncol 15, 47–62 (2018). https://doi.org/10.1038/nrclinonc.2017.148

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