Immunotherapy-related cognitive impairment after CAR T cell therapy in mice

Persistent central nervous system (CNS) immune dysregulation and consequent dysfunction of multiple neural cell types is central to the neurobiological underpinnings of a cognitive impairment syndrome, colloquially referred to as “brain fog”, that can occur following traditional cancer therapies or certain infections. Immunotherapies have revolutionized cancer care for many tumor types, but the potential long-term cognitive sequelae are incompletely understood. Here, we demonstrate in mouse models that chimeric antigen receptor (CAR) T-cell therapy for both CNS and non-CNS cancers can impair cognitive function and induce a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis are disrupted. Single nucleus sequencing studies of human frontal cortex and subcortical white matter from brain tumor patients with or without previous CAR T-cell therapy confirm reactive states of microglia and oligodendrocytes in patients treated with CAR T cell therapy. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescues oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T-cell therapy. Taken together, these findings illustrate similar mechanisms underlying immunotherapy-related cognitive impairment (IRCI) and cognitive impairment following traditional cancer therapies and other immune challenges.