Biology-driven therapies of CAR T immune effector cell-associated neurotoxicity syndrome

Chimeric antigen receptor (CAR) T cell therapy, particularly CD19-directed CAR T cells, can induce immune effector cell-associated neurotoxicity syndrome (ICANS), leading to significant morbidity and the need for immunosuppressive treatment. In this review, we discuss the molecular mechanisms leading to ICANS, drawing insights from various preclinical models and translational studies. We discuss pathophysiologic insights of ICANS from B-cell lymphoma-bearing mouse models, highlighting key differences between syngeneic and xenogeneic systems. Additionally, we review diagnostic methods to detect ICANS such as MRI, CSF analyses, and translocator-protein-positron-emission-tomography (TSPO-PET). Furthermore, we summarize current treatment recommendations and emerging therapeutic strategies aimed at mitigating ICANS. In summary, we provide a comprehensive overview of ICANS-pathophysiology, diagnostic approaches, and treatment interventions, with a focus on controlling immune dysregulation to prevent neurological complications.