ABSTRACT: Chimeric antigen receptor (CAR) T-cell therapy is a highly effective new treatment for relapsed and refractory hematological cancers but is associated with the novel treatment-limiting toxicities of cytokine release syndrome and neurotoxicity. Neurotoxicity, now more commonly referred to as immune effector cell-associated neurotoxicity syndrome (ICANS), is a clinical and neuropsychiatric syndrome that can occur in the days to weeks following CAR T-cell and other T-cell-engaging therapies. While the clinical characteristics of ICANS have been well described, its pathophysiology is poorly understood, and best treatment and preventive strategies remain elusive. Clinical trial experience and animal models suggest a central role for endothelial cell dysfunction, myeloid cells, blood-brain barrier disruption, and elevated central nervous system cytokine levels in the development of ICANS. Here we discuss ICANS incidence, clinical features, risk factors, biomarkers, pathophysiology, and grading and management.
