After treatment with car -t cells – immune cells that are designed to attack cancer – patients sometimes tell their doctors that they feel that they have “brain fog”, or forgetfulness and difficulty concentrating.
A new study guided by Stanford Medicine shows that CAR-T-cell therapy causes mild cognitive disorders, independent of other cancer treatments, and that this happens through the same cellular mechanism as cognitive impairment of two other causes: chemotherapy and respiratory infections such as flu and covid-19. The study, usually conducted in mice, which will publish online on 12 May Cellalso identifies strategies for reversing the problem.
Medications that improve brain fog will enable a better recovery of cancer immunotherapies, the researchers said.
Car-T-cell therapy is enormously promising: we see long-term survivors after Car-T cell therapy for aggressive cancers, so that patients who would otherwise have died. We must understand all its possible long-term effects, including this newly recognized syndrome of immunotherapy-related cognitive disorders, so that we can develop therapeutic approaches to repair this. “
Michelle Monje, MD, PhD, Senior author of the study, Milan Gambhir Professor in Pediatric Neuro-oncology
The main authors of the study are Anna Geraghty, PhD, Senior Staff Scientist in the Monje Lab and MD/PhD student Lehi Acosta-Alvarez.
Cognitive disorders after Car-T cell therapy is typically mild; For example, patients do not develop dementia. But it is frustrating and cannot solve itself, Monje said. With mice, her team reversed the disorders with the help of connections that are comparable to existing medicines or medicines in clinical development – which means that a treatment could be available relatively quickly, she said.
“We are deeply interested in how canch therapies influence cognition because it influences the quality of life of patients,” Monje said. “And this is especially important for children because their brains are still developing.”
Research into brain fog
Car-T cell therapy was approved for acute lymphatic leukemia in 2017. The treatment includes the removal of some of the patient’s own immune cells, known as T cells, and engineering them to attack goals on cancer cells. The modified T cells are returned to the patient’s body, where they recognize and destroy cancer.
In addition to leukemia, CAR-T cells are now used to treat other blood cancers, including multiple myeloma and some types of lymphoma, and they are tested in clinical examinations on various fixed tumors. Monje and her colleagues have a continuous test with Car-T cells for deadly brainstem and spinal cord tumors in children who are starting to show success.
Although patients report brain fog after Car-T cell therapy, studies are to measure how many cognitive disorders the therapy are only on the rise.
The research team wanted to gain an extensive insight into the situations in which CAR-T-cell therapy can cause cognitive disorders. They studied mice with tumors induced in the brain, blood, skin and bone. The researchers wanted to understand the influence on the cognition of CAR-T-cell treatment in combination with the location of the tumors (from, spreading to or outside the brain), as well as the extent to which the designed cells designed additional, associated immune response. Before and after CAR-T cell treatment, the researchers used standard cognitive tests on the mice, measuring how mice responded to a new object and navigated a simple maze.
Car-T-therapy caused a mild cognitive impairment in mice with cancers that come from, metastasis to and located completely outside the brain. The only tested mice that did not develop cognitive impairment after Car-T treatment were those with bone cancer that cause minimal extra inflammation that go beyond the cancer control activity of the CAR-T cells.
“This is the first study that demonstrates that immunotherapy in itself is sufficient to cause permanent cognitive symptoms,” Monje said. “It is also the first article to discover the mechanisms. We found exactly the same pathophysiology that we have seen in brain missen’s syndromes that occur after chemotherapy, radiation and mild respiratory covid-19 or flu.”
The researchers have shown that the immune cells of the brain, called Microglia, are important players in the problem. First the microglia are activated by the body’s immune response. The activated, “irritated” microglia produce inflammatory immune molecules known as cytokines and chemokines, which in turn have widespread effects in the brain. They are particularly harmful to oligodendrocytes, the brain cells responsible for making myelin, the cool substance that insulates nerve fibers and nerves helps to transfer signals more efficiently. Reduction of nerves isolation translates into cognitive impairment.
The scientists also analyzed samples of brain tissue of human test subjects who participated in the continuous clinical test of the team with Car-T cells for spinal cord and brain stem tumors. With the help of post-mortem fabric samples, the researchers confirmed that microglia and oligodendrocytes seem to be disrupted in the same way that the team had observed in mice after car-t-therapy.
In mice, the research team tested strategies to solve cognitive problems. They gave a compound that for a period of two weeks exhausted microglia in the brain of the mice. After that temporary exhaustion, the microglia returned to the brain in a normal, non-reactive state. The mice were no longer cognitively affected.
The researchers also gave the mice a medicine that enters the brain and interferes with signals from harmful chemokines, which blocks a specific receptor for these molecules.
“That alone saved cognition,” Monje said, that the researchers are now investigating how they can safely translate the two strategies – temporarily exhausting microglia or interrupting chemokine signals – in people who have had CAR -T -cell therapy.
“This research also illustrates that there is a uniting principle that underlies the brain missen syndromes,” Monje said. “And this specific study is so exciting because we have not only identified the cells that are central to this pathophysiology, we have found a molecular target that we can investigate to treat it.”
Researchers from the Grossman School of Medicine of New York University also contributed to the research.
The research was supported by subsidies from the Gatsby Charitable Foundation, the Howard Hughes Medical Institute Emerging Pathogens Initiative, A National Institutes of Health Director’s Pioneer Award (DP1NS11132), The National Cancer Institute (P50CA165, R01CA263500 and U19CA2olocolocolococoloDoToLOGOLODOLOCOALLOLOGOLOCOGRAALGRAAL), The National Eye Institute (R01EY03353), The California) Institute force 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 Chammbers-Okamura, the Directorate-Okamura, Het The Directorate-Okamura, The Directorate-Okamura The Virginia and DK 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 Neurodation Consortium.
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Journal Reference:
Geraghty, ac, et Alt Alto. (2025). Immunotherapy-related cognitive disorders after car T cell therapy in mice. Cell. doi.org/10.1016/J.Cell.2025.03.041.