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. STATEMENT OF SIGNIFICANCE: This manuscript examines central nervous system immune dynamics in a patient developing parkinsonism after ciltacabtagene autoleucel. A longitudinal real-world dataset of cerebrospinal fluid (n = 8) and peripheral blood (n = 6) from six matched timepoints was analysed using single-cell RNA/TCR sequencing over six months, capturing disease onset and progression.