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Neurotoxicity Associated with CD19-Targeted CAR-T Cell Therapies

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Abstract

Neurotoxicity is an important and common complication of chimeric antigen receptor-T cell therapies. Acute neurologic signs and/or symptoms occur in a significant proportion of patients treated with CD19-directed chimeric antigen receptor-T cells for B-cell malignancies. Clinical manifestations include headache, confusion, delirium, language disturbance, seizures and rarely, acute cerebral edema. Neurotoxicity is associated with cytokine release syndrome, which occurs in the setting of in-vivo chimeric antigen receptor-T cell activation and proliferation. The mechanisms that lead to neurotoxicity remain unknown, but data from patients and animal models suggest there is compromise of the blood–brain barrier, associated with high levels of cytokines in the blood and cerebrospinal fluid, as well as endothelial activation. Corticosteroids, interleukin-6-targeted therapies, and supportive care are frequently used to manage patients with neurotoxicity, but high-quality evidence of their efficacy is lacking.

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Authors and Affiliations

  1. Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA, USA

    Juliane Gust

  2. Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, WA, USA

    Juliane Gust

  3. Department of Pediatrics, University of Southern California, Los Angeles, CA, USA

    Agne Taraseviciute

  4. Clinical Research Division and Integrated Immunotherapy Research Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Cameron J. Turtle

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

    Cameron J. Turtle

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Cameron J. Turtle receives research funding from Juno Therapeutics/Celgene and Nektar Therapeutics; has served on advisory boards for Juno Therapeutics/Celgene, Nektar Therapeutics, Precision Biosciences, Caribou Biosciences, Eureka Therapeutics, Gilead, and Aptevo; and has options in Precision Biosciences, Eureka Therapeutics and Caribou Biosciences. Juliane Gust and Agne Taraseviciute have no conflicts of interest that are directly relevant to the contents of this article.

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Gust, J., Taraseviciute, A. & Turtle, C.J. Neurotoxicity Associated with CD19-Targeted CAR-T Cell Therapies. CNS Drugs 32, 1091–1101 (2018). https://doi.org/10.1007/s40263-018-0582-9

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