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Noncanonical and mortality-defining toxicities of CAR T cell therapy

Nature Medicine volume 31, pages 2132–2146 (2025)Cite this article

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Abstract

Chimeric antigen receptor (CAR) T cell therapy is associated with a unique spectrum of toxicities that drive morbidity, mortality and patient quality of life. Previous efforts yielded consensus grading systems for the prototypical immunotoxicities—namely, cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These grading systems set the stage for severity-based and standardized treatment protocols that have contributed to a reduction in the acute toxicity burden of CAR T cell therapy and have enabled outpatient administration. However, understanding of CAR T cell therapy has since grown to encompass new targets, new diseases and broader patient populations—including long-term survivors. As side effects are better defined and novel toxicities emerge, there is a need to understand their mechanisms and standardize reporting to improve clinical management. Here we review the current state of knowledge for mortality-defining and rare toxicities of CAR T cell therapies, beyond CRS and ICANS. We discuss mechanisms, including on-target injury, cytokine-associated inflammation and dysregulated recovery, and how these mechanisms affect the timing and management of toxicities. Finally, we define key unmet needs and delineate future priorities and research directions.

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Fig. 1: Timing of mortality-defining CAR T cell-related toxicities.
Fig. 2: Identification and description of emerging toxicities following CAR T cell therapy.
Fig. 3: Major immune deficits and associated infectious sequelae following CAR T cell therapy.
Fig. 4: Distribution and proposed pathophysiology of SPMs arising after CAR T cell therapy.

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Acknowledgements

K.R. acknowledges funding from the Else Kröner Forschungskolleg (EKFK) within the Munich Clinician Scientist Program (MCSP). This work was further supported by a grant from the Bruno and Helene Jöster Foundation (to K.R.) and the ‘CAR-T Control’ translational group within the Bavarian Center for Cancer Research (BZKF-TLG-22, to K.R.). M.D.J. is supported by the Mark Foundation and the Bankhead-Coley Cancer Biomedical Research Program.

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Authors and Affiliations

  1. Department of Medicine III – Hematology/Oncology, LMU University Hospital, LMU Munich, Munich, Germany

    Kai Rejeski

  2. Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Kai Rejeski

  3. German Cancer Consortium (DKTK), Partner Site Munich, a partnership between the DKFZ Heidelberg and LMU University Hospital, Munich, Germany

    Kai Rejeski

  4. Vaccine and Infectious Disease Division and Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Joshua A. Hill

  5. Department of Medicine, University of Washington, Seattle, WA, USA

    Joshua A. Hill

  6. Division of Blood and Marrow Transplantation and Cellular Therapy, Stanford University School of Medicine, Stanford, CA, USA

    Saurabh Dahiya

  7. Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA

    Michael D. Jain

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Contributions

Conceptualization: K.R.; Investigation: K.R., J.A.H., S.D. and M.D.J.; Formal analysis and visualization: K.R.; Methodology: K.R., J.A.H., S.D. and M.D.J.; Writing—original draft: K.R., J.A.H., S.D. and M.D.J.; Writing—review and editing: K.R., J.A.H., S.D. and M.D.J. All authors read and approved the final manuscript.

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Correspondence to Kai Rejeski.

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Competing interests

K.R.: Kite/Gilead: research funding, consultancy, honoraria and travel support; Novartis: honoraria; BMS/Celgene: consultancy, honoraria; Pierre-Fabre: travel support. J.A.H.: research funding: Allovir, Geovax, Takeda and Gilead; consultancy: Allovir, CSL Behring, Geovax, Karius, Gilead and Moderna. S.D.: research funding: Kite Pharma/Gilead, Novartis and Kyverna Therapeutics; advisory board/consulting: Kite Pharmaceuticals/Gilead Pharma, Bristol Myers Squibb, Incyte, Adaptive Biotechnologies. M.D.J.: Kite/Gilead: consultancy/advisory, research funding; Novartis: consultancy/advisory; Incyte: research funding; Lilly: research funding. None of these competing interests were related to the financing of this study.

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Nature Medicine thanks Roch Houot, Marco Ruella and Jay Spiegel for their contribution to the peer review of this work. Primary Handling Editor: Karen O’Leary, in collaboration with the Nature Medicine team.

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Rejeski, K., Hill, J.A., Dahiya, S. et al. Noncanonical and mortality-defining toxicities of CAR T cell therapy. Nat Med 31, 2132–2146 (2025). https://doi.org/10.1038/s41591-025-03813-5

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