After treatment with CAR-T cells — immune cells engineered to attack cancer — patients sometimes tell their doctors they feel like they have "brain fog," or forgetfulness and difficulty concentrating.
A new Stanford Medicine-led study shows that CAR-T cell therapy causes mild cognitive impairments, independent of other cancer treatments, and that this happens via the same cellular mechanism as cognitive impairment from two other causes: chemotherapy and respiratory infections such as flu and COVID-19. The study, conducted mostly in mice, which will publish online May 12 in Cell, also identifies strategies for reversing the problem.
Medications that ameliorate brain fog will enable better recovery from cancer immunotherapies, the researchers said.
"CAR-T cell therapy is enormously promising: We are seeing long-term survivors after CAR-T cell therapy for aggressive cancers, saving patients who would otherwise have died," said the study's senior author, Michelle Monje , MD, PhD, the Milan Gambhir Professor in Pediatric Neuro-Oncology. "We need to understand all its possible long-term effects, including this newly recognized syndrome of immunotherapy-related cognitive impairment, so we can develop therapeutic approaches to fix it."
The study's lead authors are Anna Geraghty, PhD, senior staff scientist in the Monje lab, and MD/PhD student Lehi Acosta-Alvarez.
Cognitive impairment after CAR-T cell therapy is typically mild; patients are not developing dementia, for instance. But it is frustrating and may not resolve on its own, Monje said. In mice, her team reversed the impairment using compounds similar to existing medications or medications in clinical development — meaning a treatment could be available relatively quickly, she said.
"We're deeply interested in how cancer therapies affect cognition because it affects patients' quality of life," Monje said. "And this is especially important for kids because their brains are still developing."
Investigating brain fog
CAR-T cell therapy was approved for acute lymphoblastic leukemia in 2017. The treatment involves removing some of the patient's own immune cells, known as T cells, and engineering them to attack targets 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 kinds of lymphoma, and they are being tested in clinical trials for various solid tumors. Monje and her colleagues have an ongoing trial of CAR-T cells for deadly brain stem and spinal cord tumors in children, which is beginning to show success.
Although patients report brain fog after CAR-T cell therapy, studies to measure how much cognitive impairment the therapy causes are only just emerging.
The research team wanted to get a comprehensive understanding of the situations in which CAR-T cell therapy might cause cognitive impairment. They studied mice that had tumors induced in the brain, blood, skin and bone. The researchers wanted to understand the influence on cognition of CAR-T cell treatment in combination with the tumors' location (originating in, spreading to or staying outside the brain), as well as the degree to which the engineered cells evoked additional, accompanying immune responses. Before and after CAR-T cell treatment, the researchers used standard cognitive tests on the mice, measuring how mice responded to a novel object and navigated a simple maze.
CAR-T therapy caused mild cognitive impairment in mice with cancers originating in, metastasizing to and located completely outside the brain. The only mice tested that did not develop cognitive impairment after CAR-T treatment were those that had bone cancer that causes minimal additional inflammation beyond the cancer-fighting activity of the CAR-T cells.
"This is the first study to demonstrate that immunotherapy on its own is sufficient to cause lasting cognitive symptoms," Monje said. "It's also the first paper to uncover the mechanisms. We found the exact same pathophysiology we've seen in brain fog syndromes that occur after chemotherapy, radiation, and mild respiratory COVID-19 or influenza."
The researchers demonstrated that the brain's immune cells, called microglia, are key players in the problem. First, the microglia become activated by the body's immune response. The activated, "annoyed" microglia produce inflammatory immune molecules known as cytokines and chemokines, which in turn have widespread effects throughout the brain. They are particularly harmful for oligodendrocytes, the brain cells responsible for making myelin, the fatty substance that insulates nerve fibers and helps nerves transmit signals more efficiently. Reduction in the nerves' insulation translates into cognitive impairment.
The scientists also analyzed samples of brain tissue from human subjects who participated in the team's ongoing clinical trial of CAR-T cells for spinal cord and brain stem tumors. Using postmortem tissue samples, the researchers confirmed that microglia and oligodendrocytes appear dysregulated in the same way the team had observed in mice after CAR-T therapy.
In mice, the research team tested strategies to resolve the cognitive problems. They gave a compound that depleted microglia in the brains of the mice for a two-week period. After that transient depletion, the microglia returned in the brain in a normal, non-reactive state. The mice were no longer cognitively impaired.
The researchers also gave the mice a medication that enters the brain and interferes with signals from damaging chemokines, blocking a specific receptor for these molecules.
"That alone rescued cognition," Monje said, adding that the researchers are now exploring how to safely translate the two strategies — transiently depleting microglia or interrupting chemokine signals — in people who have had CAR-T cell therapy.
"This research further illustrates that there is a unifying principle underpinning brain fog syndromes," Monje said. "And this particular study is so exciting because not only have we identified the cells central to this pathophysiology, we've found a molecular target we can investigate to treat it."
Researchers from New York University's Grossman School of Medicine and from Washington University School of Medicine, St. Louis, also contributed to the research.
The research was supported by grants from the Gatsby Charitable Foundation, the Howard Hughes Medical Institute Emerging Pathogens Initiative, a National Institutes of Health Director's Pioneer Award (DP1NS111132), the National Cancer Institute (P50CA165962, R01CA258384, R01CA263500 and U19CA264504), the National Institute of Neurological Disorders and Stroke (F31NS135948), the National Eye Institute (R01EY033353), the California Institute for Regenerative Medicine (CLIN2-12595), 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
