Cancer immunotherapy, like CAR-T cell treatment, has transformed cancer care, but its long-term effects on the brain are still unclear. Some patients report “brain fog”—issues with memory and focus—after receiving the therapy.
A Stanford Medicine study found CAR-T cell treatment can lead to mild cognitive issues, even without other cancer treatments. This happens through the same biological pathway that causes brain fog from chemotherapy and infections like flu or COVID-19.
The research, primarily done in mice, also suggests ways to reverse the problem. Certain medications could help patients recover mentally after cancer immunotherapy.
The study’s senior author, Michelle Monje, MD, PhD, the Milan Gambhir Professor in Pediatric Neuro-Oncology, 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. 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.”
CAR-T cell therapy can cause mild cognitive issues, but it’s not as severe as dementia. Still, patients may struggle with memory and focus, and the problem might not go away independently.
Monje’s team found a way to reverse this impairment in mice using compounds similar to existing or developing medications. This means a treatment could become available fairly soon, improving recovery after cancer therapy.
CAR-T cell therapy, initially used for leukemia, is now treating other blood cancers like lymphoma and multiple myeloma, and is being tested for solid tumors. Researchers are also exploring its potential for deadly brain and spinal cord cancers in children, with early signs of success.
While patients report “brain fog” after treatment, studies on its effects on cognition are still emerging. Scientists tested mice with tumors in different locations—brain, blood, skin, and bone- to understand when and how CAR-T therapy affects brain function. The mice underwent cognitive tests before and after treatment, including object recognition and maze navigation.
Findings showed mild cognitive impairment in mice with tumors in various locations, except for bone cancer cases with minimal inflammation. This study is the first to confirm that immunotherapy alone can cause lasting cognitive symptoms, like brain fog, after chemotherapy, radiation, and mild COVID-19 or flu.
The key mechanism involves the brain’s immune cells, microglia. When activated, they release inflammatory molecules that affect the brain, particularly harming oligodendrocytes—the cells responsible for producing myelin, which insulates nerve fibers and supports cognitive function. Loss of this insulation contributes to the cognitive decline observed after CAR-T therapy.
Scientists examined brain tissue from patients in a CAR-T therapy trial for spinal cord and brain stem tumors. They found that microglia and oligodendrocytes—key brain cells—were disrupted the same way in mice treated with CAR-T cells.
To address the issue, researchers tested solutions in mice. One approach temporarily removed microglia, allowing them to return to a non-reactive state, which eliminated cognitive problems. Another used medication to block harmful chemokine signals, which also restored brain function.
Now, scientists are working on adapting these strategies for human patients, aiming to develop treatments that can counteract brain fog caused by CAR-T therapy. This discovery highlights a common biological process behind brain fog from various sources and identifies a potential target for future therapies.
Journal Reference:
- Anna C. Geraghty, Lehi Acosta- Alcarez, Maria Rotiroti et al. Immunotherapy-related cognitive impairment after CAR T cell therapy in mice. Cell. DOI: 10.1016/j.cell.2025.03.041
