Figure 1.

Pathophysiology of chimeric antigen receptor modified (CAR) T cell toxicities. CAR T cells are activated upon antigen recognition, and induce apoptosis of multiple myeloma cells by activation of Fas/FasL-pathway and releasing cytotoxic granules containing perforin and granzyme. In turn, CAR T cells activate other immune cells such as macrophages, which produce multiple cytokines simultaneously with activated CAR T cells themselves. (A) Cytokine release syndrome (CRS): The diverse cytokines cause activation of vascular endothelium. The endothelial activation plays a major role in cytokine release syndrome with fever, hypotension, and hypoxia. (B) Immune effector cell associated neurotoxicity syndrome (ICANS): The endothelial activation by multiple cytokines in blood stream results in disruption of blood-brain barrier. Subsequently, the central nervous system (CNS) is directly exposed to the cytokines in high concentrations, leading to local inflammation and secondary cytokine production by CNS itself, e.g., microglia. (C) On-target off-tumor toxicity: Healthy tissue and some other hematopoietic cells such as B cells also express the target antigen of CAR T cells. Hence, on-target off-tumor toxicities might occur, and are dependent on the selected CAR T cell target. All organ systems could be affected. BBB, blood-brain barrier; CAR T cell, chimeric antigen receptor modified T cell; CRS, cytokine release syndrome; ICANS, immune effector cell associated neurotoxicity syndrome; IL, interleukin; IFN, interferon; MCP, monocyte chemoattractant protein; MIPs, macrophage inflammatory proteins; MM, multiple myeloma; TNF, tumor necrosis factor.