Multiomic and Longitudinal Dissection of Immune Dynamics Associated with Parkinsonism after Ciltacabtagene Autoleucel Therapy

We report a fatal case of parkinsonism following treatment with ciltacabtagene autoleucel. To investigate underlying mechanisms, we performed a multi-pronged longitudinal analysis using single-cell RNA/TCR sequencing, flow cytometry, and cytokine measurements including cerebrospinal fluid (CSF) and peripheral blood samples, spanning a time over 6 months after CAR T cell therapy. Combined clinical and molecular findings revealed a biphasic immunologic process in the CSF: The early phase was characterized by a selective influx of predominantly CD4⁺ CAR T cells, accompanied by evidence of endothelial dysfunction, prior to the clinical manifestation of parkinsonism. A second phase was preceded by a locally restricted inflammatory process in the CSF. Subsequently, a rise in the CSF/serum albumin ratio indicated disruption of the blood-brain barrier, coinciding with a pronounced influx of T cells - primarily CAR T cells, but also clonally expanded, cytotoxic CD8⁺ non-CAR T cells - which was associated with neuronal injury and clinical decline.