A groundbreaking study led by researchers at Stanford Medicine has shed new light on the mysterious cognitive difficulties commonly described as “brain fog” experienced by patients following CAR-T cell therapy. While CAR-T therapy is celebrated as a transformative cancer treatment capable of saving lives where few other options remain, this research reveals that the therapy itself can induce mild but persistent cognitive impairments through mechanisms strikingly similar to those seen in chemotherapy and infectious diseases like influenza and COVID-19. These findings, derived mainly from animal models and set to be published online in the journal Cell, not only deepen understanding of the underlying neuroimmune pathways but also identify promising therapeutic targets for reversing cognitive decline.
CAR-T cell therapy, approved by the FDA in 2017 for certain blood cancers such as acute lymphoblastic leukemia, involves genetically modifying a patient’s own T cells to specifically target and destroy cancerous cells. The promise of this approach is underscored by impressive patient outcomes and long-term remissions, yet a subset of survivors report cognitive complaints, including impaired memory, difficulty concentrating, and a sense of mental cloudiness that has colloquially become known as "brain fog". Until now, the biological basis for these symptoms linked solely to immunotherapy was not clearly established.
In this pivotal study, the Stanford team, including senior author Dr. Michelle Monje, utilized advanced animal models to mimic CAR-T therapy in mice harboring tumors in various bodily compartments, including the brain, blood, skin, and bone. Remarkably, CAR-T treatment produced mild cognitive deficits irrespective of whether the tumors were located within or outside the brain, implying that immunotherapy-induced neuroinflammation does not require direct brain involvement. The only exception was mice with bone tumors that elicited minimal systemic inflammation, suggesting that the degree of immune activation influences the cognitive outcome.
Delving into the neurobiological mechanisms, the scientists identified microglia—the brain’s resident immune cells—as pivotal mediators in the development of cognitive dysfunction following CAR-T therapy. Upon therapy-induced systemic immune activation, microglia become chronically activated and begin secreting inflammatory molecules such as cytokines and chemokines. These proinflammatory signals adversely affect oligodendrocytes, the specialized glial cells responsible for synthesizing myelin sheaths that insulate neuronal axons. Loss of myelin integrity disrupts neural conduction efficiency, manifesting as cognitive impairment.
Supporting the translational relevance of their findings, postmortem brain tissue from human patients enrolled in an ongoing clinical trial of CAR-T therapy targeting brainstem and spinal cord tumors exhibited similar microglial activation and oligodendrocyte dysfunction patterns, mirroring those observed in the murine models. This cross-species consistency strengthens the hypothesis that immune-driven white matter injury underlies the cognitive sequelae seen in some cancer immunotherapy recipients.
Encouragingly, the Stanford researchers demonstrated that targeting the neuroimmune axis can reverse the cognitive impairments in mice. Temporary depletion of microglia using pharmacologic agents allowed for repopulation of these cells in a quiescent, non-inflammatory state, thereby restoring cognitive performance. Similarly, administering a drug capable of crossing the blood-brain barrier and selectively blocking chemokine receptor signaling effectively ameliorated cognitive deficits, highlighting a viable molecular target for therapeutic intervention.
The discovery of a unifying pathophysiological pathway that links immunotherapy-related brain fog with similar syndromes observed after chemotherapy and mild respiratory infections such as influenza and COVID-19 provides critical insight into a previously elusive phenomenon. These shared mechanisms emphasize the central role of neuroimmune interactions and myelin integrity in cognitive function, suggesting that interventions developed in this context may have broad applicability.
Dr. Monje emphasized the urgency of understanding such side effects in light of the growing use of CAR-T cell therapies and the importance of cognition for quality of life, especially in pediatric patients whose brains are still in development. Given that current therapies for brain fog remain limited, this research paves the way toward developing effective treatments that could enhance the recovery and daily functioning of cancer survivors.
The study also underscores the complexity of neuroimmune crosstalk, demonstrating that peripheral immune activation can have profound effects within the central nervous system without direct tumor involvement in the brain. This discovery challenges previous assumptions and calls for a reexamination of other immunotherapy regimens’ potential cognitive effects.
Collaborators from New York University’s Grossman School of Medicine and Washington University School of Medicine contributed expertise in immunology, neurobiology, and clinical oncology to this interdisciplinary effort. Funding support from prestigious institutions and foundations, including the Howard Hughes Medical Institute, National Cancer Institute, and others, reflects the significance attributed to this research.
On a broader scale, these findings compel the scientific and medical communities to monitor and address cognitive health proactively in patients undergoing cutting-edge cancer treatments. Furthermore, the identification of microglia and chemokine signaling as therapeutic targets may spur pharmaceutical innovation toward tailored therapies that mitigate neuroinflammation-induced cognitive impairment.
As research continues, ongoing clinical trials and translational studies will be instrumental in validating these interventions in human patients and refining treatment protocols to balance potent anti-cancer efficacy with preservation of cognitive function. The Stanford team’s work heralds a new chapter in understanding and managing the neurological side effects of cancer immunotherapy, with implications that may extend well beyond oncology.
Subject of Research: Animals
Article Title: Not specified in the provided content
News Publication Date: 12-May-2025
Image Credits: Emily Moskal/Stanford Medicine
Keywords: Cancer immunotherapy, Memory disorders
