Pathophysiologic mechanism of neurotoxicity and CRS. GM-CSF is produced by CAR T cells upon contact with tumor and serves as a communication conduit between the specific immune response of the CAR T cells and the off-target inflammatory cascade produced by myeloid lineage cells. GM-CSF acts directly on myeloid cells to expand, activate, and promote the production of other chemokines, including MCP-1/CCL2, IP-10/CXCL10, and cytokines IL-6 and IL-1. Once initiated, the inflammatory cascade can become self-perpetuating as the production of chemokines results in further expansion and trafficking of myeloid cells to the tumor bed. The positive feedback loop can result in abnormally high levels of inflammatory cytokines, endothelial activation, vascular permeability, and ultimately, NT and CRS. GM-CSF also acts directly on myeloid lineage cells to promote the expansion and trafficking of myeloid derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), which have been demonstrated to inhibit T-cell proliferation and effector functions.