"CAR-T cell clinical trial showed that among serum biomarkers associated with development with grade 3 or higher neurotoxicity, GM-CSF elevation was most significantly associated with neurotoxicity3. Recent preclinical studies have demonstrated that neurotoxicity and CRS are decreased and CAR-T cell activity is increased after inhibition of macrophage activating and monocyte activating cytokine GM-CSF with lenzilumab87,98,99. GM-CSF mutational inactivation also appears to have similar effects in CAR transduced T cells98,100. Therefore, these findings suggest that GM-CSF neutralization helps diminish neurotoxicity and reduce CRS98. In addition, deletion of tyrosine hydroxylase in a myeloid cell specific manner or inhibition of this enzyme using metyrosine results in decreased catecholamine and cytokine levels101. Preclinical evidence also suggests that IL-1 receptor antagonists reduced a form of neuroinflammation in leukemia/lymphoma mouse models treated with CD19 targeted CARs102."
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