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

Anna C Geraghty¹, Lehi Acosta-Alvarez², Maria C Rotiroti³, Selena Dutton², Michael R O'Dea⁴, Wonju Kim³, Vrunda Trivedi², Rebecca Mancusi², Kiarash Shamardani², Karen Malacon², Pamelyn J Woo², Naiara Martinez-Velez³, Theresa Pham², Noemi N Reche-Ley², Gabriel Otubu², Enrique H Castenada², Kamsi Nwangwu², Haojun Xu², Sara B Mulinyawe², Daniel B Zamler², Lijun Ni², Kevin Cross⁵, Justin Rustenhoven⁵, Jonathan Kipnis⁵, Shane A Liddelow⁶, Crystal L Mackall⁷, Robbie G Majzner⁸, Michelle Monje⁹

Affiliations

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 Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10016, USA.
⁵ Brain immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130, USA.
⁶ 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.
⁷ 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.
⁸ Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA; Center for Cancer Cellular Therapy, Stanford School of Medicine, Stanford, CA 94305, USA.
⁹ 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.

PMID: 40359942
PMCID: PMC12176077 (available on 2026-06-12)
DOI: 10.1016/j.cell.2025.03.041

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

Anna C Geraghty et al. Cell. 2025.

. 2025 Jun 12;188(12):3238-3258.e25.

doi: 10.1016/j.cell.2025.03.041. Epub 2025 May 12.

Authors

Affiliations

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 Neuroscience Institute, NYU Grossman School of Medicine, New York, NY 10016, USA.
⁵ Brain immunology and Glia (BIG) Center and Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130, USA.
⁶ 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.
⁷ 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.
⁸ Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA; Center for Cancer Cellular Therapy, Stanford School of Medicine, Stanford, CA 94305, USA.
⁹ 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.

PMID: 40359942
PMCID: PMC12176077 (available on 2026-06-12)
DOI: 10.1016/j.cell.2025.03.041

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.

Keywords: ALL; CAR T cell therapy; CRCI; DMG; IRCI; acute lymphoblastic leukemia; cancer therapy-related cognitive impairment; chemokines; diffuse midline glioma; immunotherapy-related cognitive impairment; microglia; myelin; oligodendrocytes.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests M.M. holds equity in MapLight and CARGO Therapeutics. M.M., C.L.M., and R.G.M. are inventors on a patent filed by Stanford University relevant to GD2-CAR T cell therapy for DIPG/DMG; M.M. and A.C.G. are inventors on a patent filed by Stanford University on use of CCR3 blockade for IRCI. C.L.M. holds equity in CARGO Therapeutics, Link Cell Therapies, and GBM NewCo, which are developing CAR-based therapies, and consults for CARGO, Link, Immatics, Ensoma, GBM NewCo, and Red Tree Capital. She receives research funding from Lyell and Tune Therapeutics. R.G.M. is a cofounder of and holds equity in Link Cell Therapies and CARGO Therapeutics and is a consultant for Lyell Immunopharma, NKarta, Arovella Pharmaceuticals, Innervate Radiopharmaceuticals, Aptorum Group, Gadeta, FATE Therapeutics (Data and Safety Monitoring Board), and Waypoint Bio. C.L.M. is on the advisory board for Cell.

Update of

Immunotherapy-related cognitive impairment after CAR T cell therapy in mice.
Geraghty AC, Acosta-Alvarez L, Rotiroti M, Dutton S, O'Dea MR, Woo PJ, Xu H, Shamardani K, Mancusi R, Ni L, Mulinyawe SB, Kim WJ, Liddelow SA, Majzner RG, Monje M. Geraghty AC, et al. bioRxiv [Preprint]. 2024 May 14:2024.05.14.594163. doi: 10.1101/2024.05.14.594163. bioRxiv. 2024. Update in: Cell. 2025 Jun 12;188(12):3238-3258.e25. doi: 10.1016/j.cell.2025.03.041. PMID: 38798554 Free PMC article. Updated. Preprint.

References

1. Wefel JS, Kesler SR, Noll KR, and Schagen SB (2015). Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive impairment in adults. CA Cancer J Clin 65, 123–138. 10.3322/caac.21258. - DOI - PMC - PubMed
1. Mabbott DJ, Spiegler BJ, Greenberg ML, Rutka JT, Hyder DJ, and Bouffet E (2005). Serial evaluation of academic and behavioral outcome after treatment with cranial radiation in childhood. J Clin Oncol 23, 2256–2263. 10.1200/JCO.2005.01.158. - DOI - PubMed
1. Ruark J, Mullane E, Cleary N, Cordeiro A, Bezerra ED, Wu V, Voutsinas J, Shaw BE, Flynn KE, Lee SJ, et al. (2020). Patient-Reported Neuropsychiatric Outcomes of Long-Term Survivors after Chimeric Antigen Receptor T Cell Therapy. Biol Blood Marrow Transplant 26, 34–43. 10.1016/j.bbmt.2019.09.037. - DOI - PMC - PubMed
1. Barata A, Hoogland AI, Kommalapati A, Logue J, Welniak T, Hyland KA, Eisel SL, Small BJ, Jayani RV, Booth-Jones M, et al. (2022). Change in Patients’ Perceived Cognition Following Chimeric Antigen Receptor T-Cell Therapy for Lymphoma. Transplant Cell Ther 28, 401.e401–401.e407. 10.1016/j.jtct.2022.05.015. - DOI - PMC - PubMed
1. Rogiers A, Boekhout A, Schwarze JK, Awada G, Blank CU, and Neyns B (2019). Long-Term Survival, Quality of Life, and Psychosocial Outcomes in Advanced Melanoma Patients Treated with Immune Checkpoint Inhibitors. J Oncol 2019, 5269062. 10.1155/2019/5269062. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

MeSH terms

Substances

Grants and funding