Fig. 2

Mechanisms of ICANS. A. Normal state. BBB is integral, consisting of endothelial cells with tight junctions, EBM, pericytes, PBM and endfeet of astrocytes. Tie2 on endothelial cells binds with Ang I to maintain the quiescent state of endothelium. B. ICANS. Systemically increased cytokines, such as IFN-γ, IL-6, GM-CSF and TNF, can activate brain endothelial cells to release W-P bodies and their contents, Ang II and vWF. Platelets adhere vWF to form the vWF-platelet string. Possibly because of the lack of ADAMTS13, vWF fails to be cleaved and thus causes microvascular thrombosis and consumptive coagulopathy. An increase in the Ang II/Ang I ratio can lead to endothelial activation and BBB disruption through abnormalities of the Ang-Tie2 axis. As a result, cytokines and CAR T-cells infiltrate the peripheral vascular space (PVS). Cytokines have access to pericytes, inducing pericyte stress and consequent VEGF and IL-6 release to further activate endothelial cells. CD19 CAR T-cells trigger CD19-positive pericyte depletion. Astrocytes can also be injured by cytokines, causing cell swelling, abnormal osmotic forces, and consequently cerebral edema. In addition, when stimulated by cytokines, astrocytes produce VEGF-A to aggravate the BBB disruption. The disrupted BBB allows myeloid cells to infiltrate into the brain parenchyma, cooperating with activated resident microglia to trigger the immune response in the CNS. Macrophages and microglia can also produce QA and Glu, activating NMDA receptors on synapses to induce seizures and other excitotoxicity. Cytokines may also play a role in neuronal injury