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.
A look at tissue samples
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,” said Monje, a member of the Stanford Cancer Institute. “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.”
“Stanford University, officially Leland Stanford Junior University, is a private research university in Stanford, California. The campus occupies 8,180 acres, among the largest in the United States, and enrols over 17,000 students.”
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