CAR T cells affect cognition

Abstract

Chimeric antigen receptor (CAR) T cell therapy has been associated with acute neurotoxicity syndromes and with longer-term neurological symptoms. In Cell, Geraghty et al. identify the mechanism behind long-term cognitive symptoms after CAR T cell therapy. The authors used patient-derived xenograft mouse models of central nervous system (CNS) and non-CNS cancers, and an immunocompetent mouse model of a non-CNS cancer. They tested chronic effects on CNS immune state, oligodendroglial and myelin homeostasis, hippocampal neurogenesis, and cognitive function were tested after CAR T cell immunotherapy. CAR T cell therapy resulted in impaired cognition in the mice after clearing the tumor with CAR T cell therapy. They found increased levels of cytokines and chemokines in the cerebrospinal fluid, induced white matter microglial reactivity, disrupted oligodendroglial lineage cell dynamics, and impaired hippocampal neurogenesis. In a mouse model of acute lymphoblastic leukemia, microglial depletion rescued the cognitive deficits and inhibition of the receptor CCR3 rescued microglial dysregulation, oligodendrocyte loss and improved cognitive behavioral performance.

Original reference: Cell https://doi.org/10.1016/j.cell.2025.03.041 (2025)