Early Toxicities of CAR-T Cell Therapy: Mechanisms, Prediction, and Management

Chimeric antigen receptor T (CAR-T) cell therapy has completely reshaped the therapeutic landscape for some blood cancers, including B-cell lymphoma, myeloma, and acute lymphoblastic leukemia. However, the complications associated with this powerful therapy are preventing it from being used more widely. This review explores the underlying biology, clinical signs, and current treatments for the three major early CAR-T cell therapy-associated toxicities: cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. Here, we outline key findings from preclinical animal models, data from multicenter clinical trials, and real-world patient cohort study data to delineate how infused cells and different host-derived and blood–brain barrier disruptions contribute to these adverse effects. A growing body of evidence is revealing that the patient’s own monocytes and macrophages, not just the infused CAR-T cells, may contribute to driving systemic toxicities primarily by releasing interleukin-1 (IL-1) and IL-6. A more thorough and mechanistically detailed understanding of CAR-T cell therapy-associated toxicity is needed to develop better predictive tools and treatment strategies so that patients derive the greatest antitumor benefits with the lowest risk of severe treatment-related complications.