Chimeric antigen receptor T (CAR-T) cell therapy has transformed outcomes for relapsed/refractory B-cell malignancies and is increasingly reshaping the therapeutic landscape of autoimmune disorders and solid tumors, offering curative potential where options were previously limited. Its broader deployment is, however, constrained by immune-mediated toxicities, chiefly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS spans a heterogeneous spectrum from mild aphasia and tremor to seizures, cerebral edema, coma, and death, and remains difficult to predict prospectively. As CAR-T platforms expand beyond CD19 malignancies, neurotoxicity phenotypes are also broadening beyond classical ICANS. In plasma cell dyscrasias, BCMA-directed CAR-T has been associated with delayed non-ICANS neurotoxicities, including movement and neurocognitive/behavioral symptoms, cranial nerve palsies, and peripheral neuropathic presentations. In parallel, early experiences with CAR-T and related immune effector therapies in autoimmune and neuroimmunologic diseases suggest distinct inflammatory contexts and potentially different neurotoxicity patterns, underscoring the need for indication-specific monitoring and attribution frameworks. Converging data implicate a multilayered pathophysiology involving systemic cytokine surges, disruption of the blood-brain barrier, endothelial dysfunction, and context-dependent trafficking of activated CAR-T cells and other immune effectors into the CNS with baseline neurological vulnerability and the peri-infusion inflammatory milieu likely modulating individual risk. Given the frequency of these complications, an active research effort is underway to identify clinical, functional, and biological signals that could predict and improve their management. However, most biomarkers remain investigational, lacking prospective validation and straightforward clinical utility. This review synthesizes current evidence on the epidemiology, mechanisms, and monitoring of ICANS and emerging non-ICANS syndromes, and offers a fresh perspective on integrated, multimodal risk models to enable more precise stratification and timely intervention across indications.
Keywords: CAR-T cell neurotoxicity; EEG; ICANS; MNT; neurological biomarkers; virtual brain twin.
Understanding brain side effects of CAR-T cell therapy: why they happen and how we can prevent them CAR-T cell therapy is a breakthrough treatment that can cure some blood cancers when all other options have failed. It works by reprogramming a patient’s own immune cells to recognize and destroy cancer cells. Despite these successes, many patients experience neurological side effects after receiving CAR-T cells. These effects, grouped under the term ICANS (immune effector cell-associated neurotoxicity syndrome), can range from mild confusion, tremors, or trouble speaking to more severe complications such as seizures, brain swelling, or even coma. Beyond this syndrome, these therapies can also cause other neurotoxic complications, including peripheral nervous system involvement and longer term cognitive impairment. Central neurotoxicity develops through several overlapping processes. The treatment triggers a strong release of inflammatory molecules that disrupts the blood–brain barrier, allowing inflammatory signals and immune cells to enter the brain. Once inside, brain support cells like astrocytes and microglia release substances that can damage or overstimulate nerve cells, leading to swelling and impaired brain function. Some blood vessel support cells in the brain (pericytes and vascular smooth muscle cells) may also display the CD19 marker, creating the possibility of direct, unintended damage that further weakens the blood–brain barrier. The biology behind other types of neurological dysfunction remains incompletely understood. Assessment of ICANS and other neurological complications after CAR-T cells combines bedside neurological testing, brain scans, electrophysiology testing, and sometimes spinal fluid analysis. Current treatments rely on rapid detection and anti-inflammatory medicines such as corticosteroids and biological therapies, including anti-interleukin treatments. Most cases improve with timely care, but severe ICANS can be life-threatening. Understanding these mechanisms may enable better prediction, safer therapy design, and more effective pr.
© The Author(s), 2026.