Cytokine release syndrome following chimeric antigen receptor T-cell therapy: Pathophysiology, clinical manifestations, and novel therapeutic approaches

Introduction. The introduction of chimeric antigen receptor (CAR) T-cell therapy into clinical practice has transformed international treatment standards for B-cell leukemias, lymphomas, and multiple myeloma. Alongside its high antitumor activity, CAR T-cell therapy is associated with a unique profile of adverse events, including cytokine release syndrome (CRS), immune cell-associated neurotoxic syndrome (ICANS), and macrophage activation syndrome (MAS).

Aim: To present data on the mechanisms of immune toxicity of CAR T-cell therapy, its clinical manifestations, as well as prevention and treatment strategies.

Basic information. CRS is a self-sustaining hyperinflammatory condition with a specific spectrum of clinical manifestations, driven by endothelial activation and increased permeability. Genetic predisposition to CRS is associated with polymorphisms in genes involved in immune cell adhesion and activation. Key stages of pathogenesis include hyperproduction of cytokines, particularly interleukins (IL)-1β, 6, 8, 10, and interferon-γ, reduced expression of endothelial adhesion molecules, overproduction of permeability factors, and consequent interstitial organ edema and dysfunction. Conditions closely associated with CRS include immune effector cell-associated neurotoxicity syndrome (ICANS) and macrophage activation syndrome/secondary hemophagocytic lymphohistiocytosis (MAS). Treatment of CRS is based on the use of glucocorticosteroids and anticytokine monoclonal antibodies targeting the IL-6 receptor, IL-6 itself, IL-1, and interferon-γ. However, a significant proportion of adverse outcomes are driven by ICANS and MAS. The most promising treatment approach for these conditions currently involves the use of interleukin-1 antagonists, which may mitigate these severe immune toxicities.

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