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  • Review Article
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Current understanding and management of CAR T cell-associated toxicities

Nature Reviews Clinical Oncology (2024)Cite this article

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Abstract

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of several haematological malignancies and is being investigated in patients with various solid tumours. Characteristic CAR T cell-associated toxicities such as cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are now well-recognized, and improved supportive care and management with immunosuppressive agents has made CAR T cell therapy safer and more feasible than it was when the first regulatory approvals of such treatments were granted in 2017. The increasing clinical experience with these therapies has also improved recognition of previously less well-defined toxicities, including movement disorders, immune effector cell-associated haematotoxicity (ICAHT) and immune effector cell-associated haemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), as well as the substantial risk of infection in patients with persistent CAR T cell-induced B cell aplasia and hypogammaglobulinaemia. A more diverse selection of immunosuppressive and supportive-care pharmacotherapies is now being utilized for toxicity management, yet no universal algorithm for their application exists. As CAR T cell products targeting new antigens are developed, additional toxicities involving damage to non-malignant tissues expressing the target antigen are a potential hurdle. Continued prospective evaluation of toxicity management strategies and the design of less-toxic CAR T cell products are both crucial for ongoing success in this field. In this Review, we discuss the evolving understanding and clinical management of CAR T cell-associated toxicities.

Key points

  • As clinicians have gained more experience with chimeric antigen receptor (CAR) T cell therapy, the management of cytokine-release syndrome (CRS) has improved, especially with use of the IL-6 receptor antagonist tocilizumab.

  • In addition, monitoring and treatment of immune effector cell-associated neurotoxicity syndrome (ICANS) has improved with refinements to supportive care and glucocorticoid use.

  • Movement disorders are an infrequent complication of B cell maturation antigen (BCMA)-directed CAR T cells, are difficult to manage and can be life-threatening.

  • Prolonged cytopenias, secondary haemophagocytic lymphohistiocytosis and infectious complications are increasingly well recognized, and consensus guidelines have been developed for their management.

  • New T cell malignancies have been reported after CAR T cell therapy but are exceedingly rare. Patients should be monitored for second malignancies indefinitely following CAR T cell therapy.

  • Future directions in this field include the development of less-toxic CAR T cell products.

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Fig. 1: Timeline of selected CAR T cell-related adverse events.
Fig. 2: Selected strategies for improving the safety of CAR T cells.

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Acknowledgements

The authors acknowledge intramural National Cancer Institute (NCI) funding support.

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    Jennifer N. Brudno & James N. Kochenderfer

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J.N.B. serves on the scientific advisory board of Kyverna Therapeutics (unpaid position). J.N.K. receives royalties from Kite Pharma (a Gilead company), Celgene/Bristol Myers Squibb and Kyverna Therapeutics; and research funding from Kite (a Gilead company) and Celgene/Bristol Myers Squibb.

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Brudno, J.N., Kochenderfer, J.N. Current understanding and management of CAR T cell-associated toxicities. Nat Rev Clin Oncol (2024). https://doi.org/10.1038/s41571-024-00903-0

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