To comprehensively characterize the clinical presentation and pattern of Tumor Inflammation Associated Neurotoxicity (TIAN) in CNS lymphoma (CNSL) patients treated with CD19-CAR-T cells. 

TIAN represents a unique complication of immunotherapy in brain tumor patients, but little is known about its frequency, clinical presentation and associated outcomes in CNS lymphoma patients treated with CD19-directed chimeric antigen receptor T-cells (CD19-CAR).

To comprehensively characterize the clinical presentation, imaging characteristics, and histopathological features of TIAN in a large cohort of 56 patients with CNS lymphoma treated with CD19-CAR-T cells. 

TIAN occurred in 10/56 (17.9%) of CNSL with clinical onset at a median 3.5 days (range: 1-9) after CD19-CAR infusion. TIAN was less frequently associated with cytokine release syndrome (60% vs 100%, p = 0.009) than immune effector cell-associated neurotoxicity syndrome (ICANS). Larger brain tumor volume at baseline allowed the identification of patients at risk for TIAN (AUC: 0.847, p = 0.002). Presence of TIAN correlated with higher overall response rates (ORR) to CD19-CAR (90% vs 52%, p = 0.036) and improved progression-free survival (PFS) (Hazard ratio: 0.22; 95%-Confidence interval: 0.07-0.61, p = 0.006) on multivariate Cox proportional hazard regression. Post-mortem histopathological evaluation of a TIAN lesion revealed a dense macrophage population with central necrosis and peripheral reactive gliosis, accompanied by loss of white matter and intracytoplasmic myelin in foamy macrophages. 

Our work supports TIAN as a localized on-tumor, on-target neurotoxicity syndrome, closely related to pre-existing CNSL lesions. Larger CNS lymphoma tumor volume at baseline is predictive of TIAN occurrence after CD19-CAR T-cell therapy, and presence of TIAN correlated with improved overall response rates and progression-free survival.