The CXCL16/CXCR6 axis is linked to immune effector cell-associated neurotoxicity in chimeric antigen receptor (CAR) T cell therapy

Immune effector cell-associated neurotoxicity syndrome (ICANS) is a significant complication of CAR T-cell therapy, affecting 20% to 70% of patients. Unraveling the mechanisms underlying ICANS is crucial for improving patient outcomes. This study employed single-cell RNA sequencing (scRNA-seq) to analyze cerebrospinal fluid (CSF) cells from ICANS patients, uncovering a ICANS-specific increase in proliferating T cells compared to controls that contained both CAR and non-CAR expressing cells indicating bystander activation. These ICANS-specific proliferating T cells showed elevated expression of cytotoxic genes and the chemokine receptor gene CXCR6. Spatial transcriptomic mapping of postmortem choroid plexus and brain parenchyma of a patient with lethal ICANS revealed widespread myeloid cell infiltration and the spatial association of CXCR6+ T cells to CXCL16-expressing myeloid cells. These findings suggest that the CXCL16/CXCR6 axis may drive the recruitment of cytotoxic CAR CD4 T cells to the central nervous system during ICANS, potentially contributing to its pathogenesis and suggesting diagnostic and therapeutic potential. We analyzed scRNA-seq data of cerebrospinal fluid (CSF) samples from CAR T cell–treated patients who developed ICANS (n=5) within 5–21 days post-infusion. ICANS severity was graded as follows: grade 1 (n=1), grade 2 (n=2), grade 3 (n=1), and grade 4 (n=1). Control samples were obtained from patients with idiopathic intracranial hypertension and functional neurological disorders. We performed spatial transcriptomics (Visium HD) on postmortem choroid plexus and brain tissue from a patient with fatal grade 4 ICANS.