Figure 2.

Proposed pathophysiology of CRS/ICANS. Activation of CAR T-cells upon encountering its cognate antigen on a target cell results in the CAR T-cell release of granzyme, perforin, IFN-α, IFN-γ, and GM-CSF. These cytokines trigger several events on the surrounding cells. In the cancer cell, granzyme results in the activation of caspase-3 which activates gasdermin E that leads to pyroptosis of the cancer cell. The subsequently released DAMPs bind to receptors on macrophages leading to caspase-1 activation which activates gasdermin D that results in activation of an inflammatory response. The released IL-1, IL-6, catecholamines, and NO lead to several different effects. This inflammatory program can also be promoted by GM-CSF, IFN-α, and IFN-γ released by CAR T-cells. IFN-α and IFN-γ can also activate endothelial cells leading to the release of IL-6, vWF, and Ang-2, which lead to several changes affecting the vasculature. CAR, chimeric antigen receptor; Ang-2, Angiopoietin 2; IFN-γ, interferon-gamma; IFN-a, interferon-alpha; vWF, von Willebrand factor; GM-CSF, Granulocyte-macrophage colony-stimulating factor; GSDME; Gasdermin E; GSDMD, Gasdermin D; DAMPs, Damage-associated molecular patterns; NO, nitric oxide.