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Neurological complications of CAR T cell therapy for cancers

Nature Reviews Neurology volume 21, pages 422–431 (2025)Cite this article

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Abstract

Genetically engineered chimeric antigen receptor (CAR) T cells have emerged as a powerful treatment option in patients with B cell malignancies, but neurological adverse effects are common and hamper the success of such therapies. Immune effector cell-associated neurotoxicity syndrome encompasses a wide range of acute neurological adverse effects, including encephalopathy with alterations in cognition and behaviour, language, motor function and coordination. In patients treated with CAR T cells for CNS malignancies, a more localized on-tumour, on-target neurotoxicity syndrome termed tumour inflammation-associated neurotoxicity can develop acutely, resulting in localized oedema with mass effect or in electrophysiological dysfunction with neurological symptoms. Following B cell maturation antigen-targeting CAR T cell therapies, delayed neurological complications, including cranial nerve palsies and a unique delayed-onset parkinsonism syndrome, are increasingly recognized. Management of neurological complications includes symptomatic treatments such as antiepileptic drugs or cerebrospinal fluid diversion, temporary immunosuppression with corticosteroids, various cytokine-targeting agents, and other distinct approaches depending on the nature of the toxicity. As our understanding of the mechanisms that contribute to the various neurological adverse effects of CAR T cell and other T cell-engaging therapies increases, novel treatment strategies to alleviate symptoms, as well as innovative CAR designs, promise to improve the safety and neurotoxicity of these powerful immunotherapies.

Key points

  • Chimeric antigen receptor (CAR) T cell therapies for cancers are associated with a wide range of both acute and delayed neurological adverse events, and the underlying mechanisms of such diverse complications remain incompletely understood.

  • Immune effector cell-associated neurotoxicity syndrome, classically presenting with encephalopathy, is the most common acute neurological complication but is usually fully reversible.

  • Tumour inflammation-associated neurotoxicity is a distinct form of localized neurotoxicity syndrome that is uniquely seen in patients treated for CNS malignancies.

  • Delayed-onset neurotoxicities, such as cranial nerve palsies, peripheral neuropathies or parkinsonism, occur particularly with B cell maturation antigen-targeting CAR T cell therapies, can be irreversible and are the most challenging in clinical practice.

  • Current management strategies mostly rely on supportive care, corticosteroids and cytokine inhibitors, although their effectiveness varies depending on the type and timing of the underlying neurotoxicity syndrome.

  • Future directions to limit the most severe forms of neurotoxicity could include novel CAR designs with safety switches, and controlled trials testing neuroprotective interventions will allow us to better understand and potentially prevent these conditions and improve patient outcomes.

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Fig. 1: Relative timescales for onset of chimeric antigen receptor (CAR) T cell-mediated neurotoxicities.
Fig. 2: Potential pathological mechanisms and treatment approaches for chimeric antigen receptor (CAR) T cell-mediated neurotoxicities.

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  1. Division of Neuro-Oncology, Department of Neurology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA

    Philipp Karschnia & Jörg Dietrich

  2. Department of Neurosurgery, Friedrich-Alexander-University, Erlangen-Nuernberg, Germany

    Philipp Karschnia

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P.K. has served as a consultant for the American Society of Clinical Oncology. J.D. has served as a consultant and on advisory boards for Amgen, Novartis, Janssen and Johnson & Johnson. He has received research support from Ono Pharmaceuticals and royalties from Wolters Kluwer.

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Karschnia, P., Dietrich, J. Neurological complications of CAR T cell therapy for cancers. Nat Rev Neurol 21, 422–431 (2025). https://doi.org/10.1038/s41582-025-01112-8

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