Fig. 1

Risk factors for CRS and neurotoxicity. Disease burden and infused CAR-T cell dose have a direct impact on the in vivo CAR-T cell expansion. Enhanced in vivo CAR-T cell expansion also correlates with the high-intensity lymphodepletion with fludarabine, which can result in greater lymphodepletion and prevention of the anti-CAR immune responses. The level of IL-15, one of the cytokines that can improve T cell activation and function, is elevated due to the greater lymphodepletion. Patients with preexisting endothelial cell activation are prone to develop severe CRS and/or neurotoxicity. VWF released by the activated endothelial cell can bind activated endothelium and sequesters platelets. Ang-2, another endothelial cell activation biomarker, can promote the capillary leak. Moreover, activated endothelial cell is a key resource of IL-6 in CRS, and then secreted IL-6 can further facilitate endothelial cell activation, increasing the risk of CRS and/or neurotoxicity. CRS: cytokine release syndrome; CAR-T: chimeric antigen receptor T cell; IL: interleukin; VWF: von Willebrand Factor; Ang:angiopoietin