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

UNLABELLED: We report a fatal case of parkinsonism following treatment with ciltacabtagene autoleucel (cilta-cel). To investigate underlying mechanisms, we performed a multipronged longitudinal analysis using single-cell RNA (scRNA)/T-cell receptor (TCR) sequencing, flow cytometry, and cytokine measurements including cerebrospinal fluid (CSF) and peripheral blood (PB) samples, spanning more than 6 months after chimeric antigen receptor (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 the 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, an increase in the CSF to 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.

SIGNIFICANCE: This article examines central nervous system immune dynamics in a patient developing parkinsonism after cilta-cel. A longitudinal real-world dataset of CSF (n = 8) and PB (n = 6) from six matched time points was analyzed using scRNA/TCR sequencing over 6 months, capturing disease onset and progression.