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 study led by scientists at Stanford School of Medicine has now shown that CAR-T cell immunotherapy can cause mild cognitive impairments, independent of other cancer treatments, and that this happens via the same cellular mechanism associated with cognitive impairment from chemotherapy and respiratory infections such as flu and COVID-19. The study, conducted primarily in mouse models, also identified potential strategies for reversing the problem.
In mice, the team reversed the impairment using compounds similar to existing medications or those in clinical development, indicating that a treatment could be available relatively quickly, noted study lead Michelle Monje, MD, PhD, the Milan Gambhir Professor in Pediatric Neuro-Oncology. “We’re deeply interested in how cancer therapies affect cognition because it affects patients’ quality of life. And this is especially important for kids because their brains are still developing.”
Medications that ameliorate brain fog will enable better recovery from cancer immunotherapies, the researchers suggested. 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. “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.”
Senior author Monje, together with lead authors Anna Geraghty, PhD, a senior staff scientist in the Monje lab, and MD/PhD student Lehi Acosta-Alvarez, and colleagues reported on their findings in Cell, in a paper titled, “Immunotherapy-related cognitive impairment after CAR T cell therapy in mice,” in which they concluded that their collective findings “… illustrate targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.”
Cancer therapy-related cognitive impairment (CRCI) affects a large number of cancer survivors, and while traditional cancer therapies such as cytotoxic chemotherapy are frequently associated with a syndrome of persistent cognitive impairment, “… early reports suggest that immunotherapies may also increase the risk of persistent cognitive symptoms,” the authors wrote.
CAR-T cell therapy was approved for acute lymphoblastic leukemia in 2017. The treatment involves removing some of the patient’s own T cells, engineering them to attack targets on cancer cells, and then returning the modified T cells to the patient’s body, where they recognize and destroy cancer.
CAR-T cells are now used to treat other blood cancers in addition to leukemia, 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. “Understanding the mechanistic underpinnings of potential long-term cognitive symptoms is important to optimize quality of life for patients who benefit from this often life-saving cancer therapy,” the investigators noted.
Through their newly reported research, the team wanted to get a comprehensive understanding of the situations in which CAR-T cell therapy might cause cognitive impairment. Studying mice that had tumors induced in the brain, blood, skin and bone, the scientists 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.
“Thus, to assess the neurobiological consequences of CAR T cell therapy after the acute period of tumor clearance, we tested the chronic effects of CAR T cell immunotherapy for malignancies within and outside of the nervous system on CNS immune state, oligodendroglial/myelin homeostasis, hippocampal neurogenesis, and cognitive function in preclinical mouse models,” they stated. Before and after CAR-T cell treatment, the researchers used standard cognitive tests on the mice, measuring how the mice responded to a novel object and navigated a simple maze.
Their results showed that 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 caused minimal additional inflammation beyond the cancer-fighting activity of the CAR-T cells.
Further investigation demonstrated that the brain’s microglia immune cells are key players in the mechanism underlying the cognitive problems. The team found that first, the microglia become activated by the body’s immune response. These activated microglia then produce inflammatory 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. “… we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines,” they stated.
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 that the team had observed in mice after CAR-T therapy. “Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes post treatment,” they wrote.
“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.”
In mice, the research team tested strategies to resolve the cognitive problems. They administered a compound that depleted microglia in the brains of the mice for a two-week period. “To deplete microglia, we used a small-molecule inhibitor of colony-stimulating factor 1 receptor (CSF1R), PLX5622,” they explained. 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. “In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy,” the team noted in their report.
Monje said 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.”
The post CAR-T Cell Therapy-Related “Brain Fog” Mechanism and Treatment Approaches Identified appeared first on GEN - Genetic Engineering and Biotechnology News.
In mice, the team reversed the impairment using compounds similar to existing medications or those in clinical development, indicating that a treatment could be available relatively quickly, noted study lead Michelle Monje, MD, PhD, the Milan Gambhir Professor in Pediatric Neuro-Oncology. “We’re deeply interested in how cancer therapies affect cognition because it affects patients’ quality of life. And this is especially important for kids because their brains are still developing.”
Medications that ameliorate brain fog will enable better recovery from cancer immunotherapies, the researchers suggested. 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. “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.”
Senior author Monje, together with lead authors Anna Geraghty, PhD, a senior staff scientist in the Monje lab, and MD/PhD student Lehi Acosta-Alvarez, and colleagues reported on their findings in Cell, in a paper titled, “Immunotherapy-related cognitive impairment after CAR T cell therapy in mice,” in which they concluded that their collective findings “… illustrate targetable neural-immune mechanisms underlying immunotherapy-related cognitive impairment.”
Cancer therapy-related cognitive impairment (CRCI) affects a large number of cancer survivors, and while traditional cancer therapies such as cytotoxic chemotherapy are frequently associated with a syndrome of persistent cognitive impairment, “… early reports suggest that immunotherapies may also increase the risk of persistent cognitive symptoms,” the authors wrote.
CAR-T cell therapy was approved for acute lymphoblastic leukemia in 2017. The treatment involves removing some of the patient’s own T cells, engineering them to attack targets on cancer cells, and then returning the modified T cells to the patient’s body, where they recognize and destroy cancer.
CAR-T cells are now used to treat other blood cancers in addition to leukemia, 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. “Understanding the mechanistic underpinnings of potential long-term cognitive symptoms is important to optimize quality of life for patients who benefit from this often life-saving cancer therapy,” the investigators noted.
Through their newly reported research, the team wanted to get a comprehensive understanding of the situations in which CAR-T cell therapy might cause cognitive impairment. Studying mice that had tumors induced in the brain, blood, skin and bone, the scientists 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.
“Thus, to assess the neurobiological consequences of CAR T cell therapy after the acute period of tumor clearance, we tested the chronic effects of CAR T cell immunotherapy for malignancies within and outside of the nervous system on CNS immune state, oligodendroglial/myelin homeostasis, hippocampal neurogenesis, and cognitive function in preclinical mouse models,” they stated. Before and after CAR-T cell treatment, the researchers used standard cognitive tests on the mice, measuring how the mice responded to a novel object and navigated a simple maze.
Their results showed that 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 caused minimal additional inflammation beyond the cancer-fighting activity of the CAR-T cells.
Further investigation demonstrated that the brain’s microglia immune cells are key players in the mechanism underlying the cognitive problems. The team found that first, the microglia become activated by the body’s immune response. These activated microglia then produce inflammatory 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. “… we demonstrated in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impaired cognitive function and induced a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines,” they stated.
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 that the team had observed in mice after CAR-T therapy. “Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes post treatment,” they wrote.
“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.”
In mice, the research team tested strategies to resolve the cognitive problems. They administered a compound that depleted microglia in the brains of the mice for a two-week period. “To deplete microglia, we used a small-molecule inhibitor of colony-stimulating factor 1 receptor (CSF1R), PLX5622,” they explained. 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. “In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescued oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy,” the team noted in their report.
Monje said 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.”
The post CAR-T Cell Therapy-Related “Brain Fog” Mechanism and Treatment Approaches Identified appeared first on GEN - Genetic Engineering and Biotechnology News.