Cytokine Release Syndrome with Chimeric Antigen Receptor T Cell Therapy

Highlights•CRS is a common, potentially life-threatening complication of CAR T cell therapy requiring close observation.•The first clinical sign of CRS is fever, which can progress to hypotension, hypoxia, and end-organ dysfunction.•In ALL, disease burden is a significant risk factor for severe CRS.•Administration of the anti-IL-6 receptor antagonist tocilizumab, with or without corticosteroids, is the mainstay of treatment. The optimal timing for intervention with tocilizumab is unknown.•Investigations are underway to identify novel approaches to prevent and abrogate CRS.AbstractChimeric antigen receptor (CAR)-modified T cells (CAR-Ts) targeting CD19 have resulted in unprecedented durable remissions for patients with relapsed and refractory B cell malignancies. Cytokine release syndrome (CRS), resulting from rapid immune activation induced by CAR-Ts, is the most significant treatment-related toxicity. CRS initially manifests with fever and can progress to life-threatening capillary leak with hypoxia and hypotension. The clinical signs of CRS correlate with T cell activation and high levels of cytokines including IL-6. Tocilizumab, an anti-IL-6 receptor antagonist, is the standard for CRS management, but optimal timing of administration is unclear. The development of a supportive infrastructure by treatment centers is important to maintain safe administration as access expands. Collaborative efforts are underway to harmonize the definition and grading of CRS to allow for better interpretation of toxicities across CAR-T products and clinical trials and allow for informed management algorithms.