Immunotherapy-related cognitive impairment after CAR T cell therapy in mice
Year: 2025
Type: article
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.
Source: Cell
Authors: Anna C. Geraghty, Lehi Acosta-Alvarez, Maria C. Rotiroti, Selena Dutton, Michael R. O’Dea, Wonju Kim, Vrunda Trivedi, Rebecca Mancusi, Kiarash Shamardani, Karen Malacon, Pamelyn J. Woo, Naiara Martinez-Velez, Theresa Pham, Noemi N. Reche-Ley, Gabriel Otubu, Enrique H. Castenada, Kamsi Nwangwu, Haojun Xu, Sara B. Mulinyawe, Daniel B. Zamler, Lijun Ni, Kevin Cross, Justin Rustenhoven, Jonathan Kipnis, Shane A. Liddelow, Crystal L. Mackall, Robbie G. Majzner, Michelle Monje
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $11,400
Funders: Howard Hughes Medical Institute, Alex's Lemonade Stand Foundation for Childhood Cancer, Virginia and D.K. Ludwig Fund for Cancer Research, Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, Cancer Research UK, Gatsby Charitable Foundation, National Institutes of Health, University of Texas MD Anderson Cancer Center, NIH Office of the Director, National Eye Institute, National Cancer Institute, National Institute of Neurological Disorders and Stroke
Awards: Neuronal activity-regulated mechanisms of glioma growth, Glioma Circuitry: Bridging Systems Neuroscience and Cancer, Neuronal Regulation of Low-Grade Gliomagenesis, Leveraging innovative technologies in basic and clinical cancer research, Training Program in Translational Brain Tumor Research, Functional interrogation of region-specific reactive astrocyte factors in neuroinflammation, Neurotoxicity of Reactive Astrocyte-secreted Lipids in Neurodegenerative Disease, Developing Safe and Effective GD2-CAR T Cell Therapy for Diffuse Midline Gliomas, Targeted Therapies for Glioma, Harvard/Stanford GTN Program: Novel targeted therapeutics for glioblastoma
OpenAlex ID: W4410314249