Summary: Patients treated with CAR-T cell therapy sometimes experience “brain fog”—difficulty concentrating, forgetfulness, and slowed thinking. New research led by Stanford Medicine shows that CAR-T therapy itself can trigger this mild cognitive impairment. In mouse models, the immune response evoked by CAR-T cells activates brain microglia, which produce inflammatory signals that harm oligodendrocytes (the cells that make myelin). Loss of myelin reduces neural signal efficiency and produces cognitive symptoms similar to those reported after chemotherapy or mild respiratory infections such as COVID-19. The study also identifies two strategies that reversed cognitive deficits in mice, suggesting possible paths toward treatments for people.
These findings clarify a common mechanism linking immunotherapy-associated brain fog with other inflammation-driven cognitive syndromes and point to actionable targets for prevention or reversal.
Key facts
- CAR-T as an independent cause: The study found CAR-T cell therapy can produce lasting, mild cognitive impairment independent of tumor location or other cancer treatments.
- Shared inflammatory pathway: Brain fog following CAR-T, chemotherapy, and mild respiratory infections appears to involve the same immune-driven pathway—microglial activation, cytokine and chemokine signaling, and injury to oligodendrocytes and white matter.
- Reversible in mice: Two interventions—transient depletion of reactive microglia and blockade of a chemokine receptor (CCR3)—restored myelin homeostasis and rescued cognitive performance in mouse behavioral tests.
Source: Stanford
Background
CAR-T cell therapy, approved in recent years for several blood cancers and under investigation for other tumors, involves genetically engineering a patient’s T cells to recognize and attack cancer cells. The treatment can be lifesaving, particularly for aggressive malignancies that previously had few options. As CAR-T use expands, clinicians and researchers are working to characterize its short- and long-term side effects—including effects on cognition and brain health.
What the study did
Researchers led by Michelle Monje, MD, PhD, used mouse models to test whether CAR-T therapy causes cognitive problems and to examine underlying mechanisms. They implanted tumors in different locations (brain, blood, skin and bone) to evaluate whether tumor site or the systemic immune response mattered for cognition. Mice underwent standard behavioral tests that measure recognition memory and navigation before and after CAR-T treatment.
CAR-T therapy produced mild but measurable cognitive impairment across models with tumors in the brain, tumors that metastasized to the brain, and tumors entirely outside the central nervous system. The only exception was a bone cancer model that provoked minimal additional inflammation beyond the direct activity of CAR-T cells.
Mechanism: microglia, inflammation and myelin injury
The team found that CAR-T–triggered immune activation stimulates microglia, the brain’s resident immune cells. Once activated, microglia secrete cytokines and chemokines that propagate inflammation throughout white matter. Those inflammatory signals impair oligodendrocytes, which produce myelin—the insulating sheath that allows rapid, efficient nerve signaling. Disruption of oligodendrocyte function and loss of myelin integrity are linked to the observed deficits in attention and short-term memory.
To corroborate the mouse data, the researchers examined postmortem brain tissue from participants in an ongoing clinical trial of CAR-T therapy for brainstem and spinal cord tumors. Single-nucleus sequencing and tissue analysis revealed microglial and oligodendroglial changes consistent with the patterns seen in mice.
Reversing the effects in mice
Importantly, the study tested interventions that reversed cognitive deficits in mice. One approach used a compound to transiently deplete microglia for about two weeks; when microglia repopulated the brain, they returned to a nonreactive state and cognitive function normalized. The other approach blocked CCR3, a chemokine receptor involved in transmitting damaging signals; CCR3 blockade alone rescued oligodendroglial health and restored performance on attention and memory tests.
Because both strategies use mechanisms already targeted by existing or clinically developing drugs, the authors note these findings could accelerate translation to human studies. The investigators emphasize careful evaluation of safety and timing when considering transient microglial modulation or chemokine-receptor blockade in people who have received CAR-T therapy.
Clinical implications
The research highlights a unifying neural-immune mechanism behind multiple forms of brain fog and suggests specific, testable interventions. Addressing CAR-T–related cognitive changes could improve quality of life and recovery for cancer survivors, including children whose developing brains may be particularly vulnerable.
The study’s lead authors are Anna Geraghty, PhD, and Lehi Acosta-Alvarez, MD/PhD student, with senior authorship by Michelle Monje, MD, PhD.
Funding
This research received support from multiple sources, including the Gatsby Charitable Foundation, the Howard Hughes Medical Institute Emerging Pathogens Initiative, the National Institutes of Health (including a Director’s Pioneer Award and several NCI and NINDS grants), the California Institute for Regenerative Medicine, the Parker Institute for Cancer Immunotherapy, CureSearch, the McKenna Claire Foundation, the Unravel Pediatric Cancer Foundation, ChadTough Defeat DIPG, Alex’s Lemonade Stand Foundation, the Yuvaan Tiwari Foundation, the Chambers-Okamura Endowed Directorship for Pediatric Neuro-Immuno-Oncology, the Virginia and D.K. Ludwig Fund for Cancer Research, the Waxman Family Research Fund, the Parekh Center for Interdisciplinary Neurology, Cure Alzheimer’s Fund, and the MD Anderson Cancer Center Neurodegeneration Consortium.
About this CAR-T and brain fog research news
Author: Erin Digitale
Source: Stanford
Contact: Erin Digitale – Stanford
Image credit: Neuroscience News
Original research (open access): Immunotherapy-related cognitive impairment after CAR T cell therapy in mice, by Michelle Monje et al., published in Cell. DOI: 10.1016/j.cell.2025.03.041
Abstract (summary)
Using mouse models, the study shows that CAR-T cell therapy for both central nervous system and non-CNS cancers can impair cognition and induce a persistent CNS immune response marked by white matter microglial reactivity, increased microglial chemokine expression, and elevated cerebrospinal fluid cytokines and chemokines. These changes disrupt oligodendroglial homeostasis and hippocampal neurogenesis. Human frontal lobe single-nucleus sequencing from patients with prior CAR-T therapy confirmed reactive microglial and oligodendroglial states. In mice, either transient microglial depletion or blockade of the CCR3 chemokine receptor restored oligodendroglial function and cognitive performance, identifying targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.