CAR T-cell therapy has changed the outlook for people with some of the most aggressive blood cancers, turning a patient’s own immune system into a living cancer-fighting drug. Yet the treatment’s extraordinary power can come with a dangerous neurological cost. A research team at the University of California, Irvine, has proposed a new strategy for preventing and treating immune effector cell-associated neurotoxicity syndrome, or ICANS, a complication that can cause confusion, speech problems, seizures, brain swelling and, in severe cases, life-threatening inflammation. In a study published in Frontiers in Pharmacology, the researchers argue that mitochondria—tiny structures responsible for cellular energy production and immune regulation—may be a central and underused target in the biology of ICANS. Their framework focuses on repurposing existing mitochondrial-targeting medicines rather than waiting for entirely new drugs to be discovered and developed.
CAR T-cell therapy begins with the removal of immune cells called T cells from a patient’s blood. In a laboratory, these cells are genetically modified to carry chimeric antigen receptors, molecular structures that allow them to recognize specific proteins on cancer cells. The engineered cells are multiplied and then infused back into the patient, where they can seek out and destroy malignant cells. This approach has produced dramatic and sometimes durable remissions in several blood cancers, including certain leukemias, lymphomas and multiple myeloma. But once activated, CAR T cells can release large quantities of inflammatory signaling molecules, including cytokines. The resulting immune cascade can affect the blood-brain barrier, alter the function of cells supporting the nervous system and allow inflammation to spread into the brain. ICANS often develops alongside or after cytokine release syndrome, another immune-related complication of CAR T-cell treatment.
The neurological symptoms of ICANS can emerge rapidly, sometimes within days of CAR T-cell infusion. Early signs may include difficulty finding words, trouble writing, reduced attention, disorientation or unusual sleepiness. As the condition progresses, patients may experience severe confusion, tremors, weakness, seizures or loss of consciousness. Clinicians monitor patients closely using neurological assessments, laboratory tests and, when necessary, brain imaging or electroencephalography. Current treatment relies heavily on corticosteroids, which suppress broad inflammatory activity and can be lifesaving. However, steroids may also produce substantial side effects, including immune suppression, metabolic disturbances, muscle weakness and psychological effects. They can also interfere with the activity of therapeutic immune cells, raising concern that controlling toxicity could come at the expense of the anticancer response. The UC Irvine researchers say a more precise, mechanism-based approach could help protect the brain while preserving the benefits of CAR T-cell therapy.
The new study places mitochondrial dysfunction at the center of that proposed mechanism. Mitochondria are best known as the organelles that generate adenosine triphosphate, or ATP, the chemical energy that powers cellular activity. They also regulate calcium balance, control programmed cell death and influence the production of inflammatory molecules. When mitochondria become damaged or overloaded, they can generate excessive reactive oxygen species, unstable molecules capable of injuring proteins, membranes and DNA. Mitochondrial stress can also alter the behavior of immune cells, pushing them toward prolonged activation and increased cytokine production. In the context of CAR T-cell therapy, the researchers suggest that this metabolic disruption could intensify systemic inflammation, weaken the protective functions of the blood-brain barrier and contribute to neuronal and glial injury. Rather than viewing ICANS solely as an uncontrolled cytokine reaction, the framework presents it as a disorder involving the interaction of immune activation, cellular metabolism and brain vascular biology.
This perspective could open the door to a different class of interventions. The authors identify mitochondrial-targeting drugs as potential steroid-sparing candidates—medications that might reduce the biological drivers of neurotoxicity without broadly shutting down the immune response. Depending on their mechanisms, such drugs could help limit oxidative stress, stabilize mitochondrial membranes, improve energy metabolism, regulate calcium handling or reduce inflammatory signaling linked to damaged mitochondria. Some compounds with these properties are already used for other medical conditions, while others have been studied in neurological, metabolic or inflammatory diseases. Repurposing them could be faster and less expensive than developing a new medicine from the beginning because existing data may already describe their absorption, dosing, toxicity and interactions with other drugs. The authors emphasize, however, that a safety history in one disease does not automatically establish safety during CAR T-cell therapy, when patients may be medically fragile and experiencing intense immune activation.
“Our work points to mitochondrial dysfunction as a promising therapeutic target for serious neurological complications of CAR T-cell therapy,” said lead author Atena Zahedi, assistant professor of clinical pharmacy practice in UC Irvine’s School of Pharmacy & Pharmaceutical Sciences. “By identifying existing drugs that may be repurposed, we hope to accelerate the development of safer treatment strategies for patients receiving these lifesaving therapies.” The proposal is especially relevant because the timing of ICANS can leave physicians with few options beyond supportive care, intensive monitoring and corticosteroids. A drug capable of interrupting mitochondrial stress early in the process could, in principle, be administered before neurological injury becomes severe. It might also be paired with current treatments, allowing clinicians to use lower steroid doses or shorten steroid exposure. Such possibilities remain hypothetical until tested in carefully designed laboratory studies and clinical trials.
For co-author Shawn Griffin, an oncology pharmacist and associate clinical professor of clinical pharmacy practice at UC Irvine, the practical appeal lies in the possibility of moving promising candidates toward patients more rapidly. “One of the greatest opportunities in this work is identifying existing drugs that may be repurposed to better manage the neurological side effects associated with CAR T-cell therapy,” Griffin said. “Because many of these medications already have established safety profiles, they could potentially move into clinical evaluation more quickly than developing entirely new drugs.” Even so, repurposing requires rigorous screening. Researchers must determine whether a candidate reaches the brain at an effective concentration, whether it interferes with CAR T-cell expansion or cancer killing, how it interacts with corticosteroids and other supportive medicines, and whether its benefits outweigh risks such as cardiac, hepatic or metabolic toxicity. Biomarkers of mitochondrial injury and inflammation could eventually help doctors identify which patients are most likely to benefit.
The research also carries a personal dimension for co-author Onwodi Ifejeokwu, who lost a family member to B-cell lymphoma in 2021. During the illness, she witnessed how cancer and its treatment could affect the brain, an experience that helped shape her interest in neuro-immuno-oncology. She now works with Zahedi, Griffin and senior author Erin Dean on research aimed at improving the quality of life of patients receiving advanced cancer therapies. Dean, a medical oncologist at UC Irvine’s Chao Family Comprehensive Cancer Center, is leading related clinical research efforts designed to evaluate new approaches to patient care. The team’s collaboration brings together clinical pharmacy, oncology and neuro-immunology, reflecting the complexity of ICANS itself. The syndrome cannot be fully understood through a single lens: immune cells, endothelial cells, neurons, glial cells, blood vessels and energy metabolism may all contribute to the final neurological outcome.
The study does not report a proven treatment or claim that mitochondrial drugs can currently prevent ICANS. Instead, it offers a translational roadmap for testing the hypothesis. Future work will need to establish which mitochondrial pathways are altered during CAR T-cell therapy, define the sequence linking immune activation to neurological symptoms and identify reliable indicators of impending toxicity. Candidate drugs must then be evaluated in cellular systems, animal models and clinical trials, with outcomes that include both neurological safety and cancer control. Investigators will also need to determine whether mitochondrial dysfunction is a primary driver of ICANS or one part of a wider network involving cytokines, vascular permeability, coagulation and blood-brain barrier disruption. If the framework withstands those tests, it could help transform ICANS management from a largely reactive effort into an earlier and more targeted intervention. For patients receiving CAR T-cell therapy, that could mean preserving the treatment’s remarkable anticancer potential while reducing one of its most frightening risks.
Subject of Research: Mitochondrial dysfunction and potential mitochondrial-targeting treatments for immune effector cell-associated neurotoxicity syndrome (ICANS) following CAR T-cell therapy.
Article Title: Repurposing mitochondrial-targeting drugs for management of ICANS in CAR T-cell therapy: a novel steroid-sparing approach
News Publication Date: Aug. 18, 2026
Web References: Frontiers in Pharmacology article; UC Irvine Chao Family Comprehensive Cancer Center; UC Irvine News
References: Frontiers in Pharmacology, article published July 27, 2026; “Repurposing mitochondrial-targeting drugs for management of ICANS in CAR T-cell therapy: a novel steroid-sparing approach.”
Keywords: CAR T-cell therapy, cancer immunotherapy, ICANS, neurotoxicity, mitochondrial dysfunction, mitochondria, cytokine release syndrome, brain inflammation, drug repurposing, steroid-sparing treatment, blood cancers, neuro-immuno-oncology
Tags: blood cancer immunotherapyCAR-T Cell TherapyICANS prevention strategiesimmune effector cell neurotoxicityimmune system regulation in cancerinnovative cancer therapy approacheslife-threatening inflammation in cancer patientsmitochondrial targeting in cancer treatmentneurological complications of cancer treatmentsneurotoxicity management in immunotherapyrepurposing mitochondrial medicinesside effects of CAR T-cell therapy
