Geraghty and Acosta-Alvarez et al. investigated mechanisms underlying impaired cognition following CAR T cell therapy for CNS and non-CNS tumors. In several mouse models, CAR T cells induced neuroinflammation with white matter microglial reactivity, increases in levels of CSF cytokines and chemokines, and dysregulation of oligodendroglial cells and hippocampal neurogenesis. RNAseq analysis of frontal lobes from CAR T cell-treated patients with brain stem tumors confirmed microglial and oligodendrocyte reactivity. In mice, transient depletion of microglia or CCR3 blockade rescued oligodendroglial deficits and improved cognitive performance.
Contributed by Katherine Turner
ABSTRACT: Immunotherapies have revolutionized cancer care for many tumor types, but their potential long-term cognitive impacts are incompletely understood. Here, we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced 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 were disrupted. Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes following treatment. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued 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 targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.
Author Info: (1) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
Author Info: (1) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. (2) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (3) Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA. (4) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (5) Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10016, USA. (6) Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA. (7) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (8) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (9) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (10) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (11) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (12) Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA. (13) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (14) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (15) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (16) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (17) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (18) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (19) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (20) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (21) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA. (22) Brain immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130, USA. (23) Brain immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130, USA. (24) Brain immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130, USA. (25) Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY 10016, USA; Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY 10016, USA. (26) Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA; Center for Cancer Cellular Therapy, Stanford School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. (27) Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA; Center for Cancer Cellular Therapy, Stanford School of Medicine, Stanford, CA 94305, USA. (28) Department of Neurology and Neurosciences, Stanford School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA; Center for Cancer Cellular Therapy, Stanford School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: mmonje@stanford.edu.
