UC Irvine researchers have developed a new framework aimed at making CAR T-cell therapy safer for patients battling aggressive blood cancers. The innovative approach focuses on targeting the biological processes believed to cause a serious neurological complication associated with this treatment.
CAR T-cell therapy has revolutionized cancer care, offering a vital option for patients who previously faced limited choices. However, this potent immunotherapy can trigger immune effector cell-associated neurotoxicity syndrome (ICANS), a potentially life-threatening complication. ICANS manifests with severe neurological symptoms, including brain inflammation, confusion, and seizures, affecting the brain and nervous system.
Currently, clinicians primarily use corticosteroids to manage the inflammation caused by ICANS. While often effective, these steroids can come with significant side effects and may not address the underlying mechanisms driving the syndrome. The UC Irvine team's research, published in *Frontiers in Pharmacology*, highlights mitochondrial dysfunction as a crucial factor contributing to ICANS.
Rather than developing entirely new medications, the researchers propose evaluating existing drugs with established safety profiles for repurposing. This strategy could significantly accelerate the timeline for clinical testing, potentially leading to improved outcomes for cancer patients more quickly. Atena Zahedi, an assistant professor of clinical pharmacy practice in UC Irvine’s School of Pharmacy & Pharmaceutical Sciences and the study’s lead author, stated that "Our work points to mitochondrial dysfunction as a promising therapeutic target" for one of CAR T-cell therapy's most serious neurological complications. She added that identifying existing drugs for repurposing could hasten the development of safer treatment strategies.
CAR T-cell therapy involves extracting a patient's immune cells, enhancing them with chimeric antigen receptors, and reintroducing them to target and destroy cancer. The intense immune response generated by this process can sometimes lead to the neurological injury observed in ICANS. The interdisciplinary UC Irvine team focused on mitochondria, the cellular structures responsible for energy production and immune regulation. Their findings indicate that dysfunctional mitochondria may intensify the inflammatory response that contributes to neurological damage after CAR T-cell therapy.
For co-author Onwodi Ifejeokwu, this research carries a personal dimension. Having lost a family member to B cell lymphoma in 2021, she witnessed firsthand the devastating impact cancer treatment can have on the brain. This personal experience fueled her dedication to neuro-immuno-oncology research, working alongside her mentors Zahedi, Dean, and Griffin to enhance the quality of life for cancer patients.
Shawn Griffin, an oncology pharmacist and associate clinical professor of clinical pharmacy practice at UC Irvine and a co-author, emphasized the practical benefit of this approach. He noted that one of the greatest opportunities in this work is "identifying existing drugs that may be repurposed" to better manage these neurological side effects. Because many of these medications already have proven safety records, they could progress into clinical evaluation more rapidly than novel drugs, thereby accelerating the discovery of safer options that preserve CAR T-cell therapy’s life-saving benefits.
The study also includes a roadmap designed to guide the translation of these findings into future clinical research. Dr. Erin Dean, a senior author and medical oncologist at UC Irvine’s Chao Family Comprehensive Cancer Center, is currently leading related clinical research efforts, aiming to evaluate new approaches that could improve patient care based on these discoveries.
