Potential mechanisms of acute myelopathy following CAR T cells. (A) Normal spinal cord and BBB. (B) Acute myelopathy after infusion of CAR T cells. Several potential mechanisms are likely involved and may interact, including: (1) inflammatory mediators disrupt the BBB and exert direct toxicity; (2) a decrease in blood flow to the spinal cord that can potentially lead to infarction can be caused by elevated intraspinal canal pressure secondary to inflammation; (3) local inflammation from an adjacent tumor causes BBB damage and neuronal cell injury (TIAN); (4) on-target off-tumor toxicity of CAR T cells. Potential targets include CD19-expressing mural cells (illustrated), which can lead to BBB disruption, and CD22-expressing oligodendrocytes, which can cause demyelination; and (5) radiation therapy damages the BBB and/or sensitizes neuronal cells to neurotoxicity; and (6) ICIs may enhance on-target off-tumor toxicities or promote increased secretion of inflammatory mediators when CAR T cells are activated at the tumor site. Other contributing factors may include tumor histology, patient sex, and age. Figure created with BioRender.com.