UC Irvine Researchers Propose Mitochondrial Dysfunction as Target to Make CAR T-Cell Therapy Safer
核心洞察
UC Irvine (搜索) researchers have identified mitochondrial dysfunction as a key contributor to immune effector cell-associated neurotoxicity syndrome (搜索) (ICANS), a life-threatening complication of CAR T-cell therapy.
The study, published in Frontiers in Pharmacology, proposes repurposing existing drugs with established safety profiles to treat ICANS rather than developing new medications.
Clinicians currently rely on corticosteroids (搜索) to manage ICANS, but these can cause significant side effects and may not address the underlying biological mechanisms.
Researchers at UC Irvine (搜索) have developed a new framework that could help make CAR T-cell therapy safer by targeting the biological processes believed to drive a potentially life-threatening neurological complication. Published in Frontiers in Pharmacology, the study stresses that mitochondrial dysfunction is a key contributor to immune effector cell-associated neurotoxicity syndrome (搜索) (ICANS) and outlines how existing drugs could potentially be repurposed to treat it.
CAR T-cell therapy has transformed cancer care, offering new hope to patients with aggressive blood cancers who once had few treatment options. But for some patients, the powerful immunotherapy can trigger a potentially life-threatening complication that causes brain inflammation, confusion, seizures and other serious neurological symptoms.
In CAR T-cell therapy, a patient's immune cells are extracted and enhanced with chimeric antigen receptors, enabling them to recognize and destroy cancer when reintroduced into the body. While the treatment has produced remarkable results for many blood cancers, the intense immune response it generates can sometimes lead to ICANS, a complication that affects the brain and nervous system.
Targeting Mitochondrial Dysfunction
Rather than developing an entirely new medication, the researchers propose evaluating drugs that already have established safety profiles, potentially accelerating the path toward clinical testing and improving outcomes for cancer patients.
"Our work points to mitochondrial dysfunction as a promising therapeutic target for serious neurological complications of CAR T-cell therapy," says lead author Atena Zahedi, assistant professor of clinical pharmacy practice in the UC Irvine (搜索) 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 interdisciplinary UC Irvine (搜索) team focused on mitochondria (搜索), the structures inside cells responsible for producing energy and regulating immune function. Their research suggests that when mitochondria become dysfunctional, they may amplify the inflammatory response that contributes to neurological injury after CAR T-cell therapy.
Limitations of Current Treatment
Today, clinicians primarily rely on corticosteroids (搜索) to control the inflammation. Although effective for many patients, steroids can produce significant side effects and may not address the underlying biological mechanisms driving ICANS.
"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," says co-author Shawn Griffin, an oncology pharmacist and associate clinical professor of clinical pharmacy practice at UC Irvine (搜索).
"Because many of these [medications] already have established safety profiles, they could potentially move into clinical evaluation more quickly than developing entirely new drugs. Our goal is to accelerate the discovery of safer treatment options that protect patients while preserving the lifesaving benefits of CAR T-cell therapy."
A Personal Motivation and Path Forward
For co-author Onwodi Ifejeokwu, this work is personal. She lost a family member in 2021 to B cell lymphoma (搜索). Over the course of treatment, she witnessed firsthand how devastating cancer treatment can be on the brain. This loss spurred her passion for neuro-immuno-oncology research. She works alongside her mentors Zahedi, Dean and Griffin to improve the quality of life for cancer patients.
The study also provides a road map for translating these findings into future clinical research. Senior author Dr. Erin Dean, a medical oncologist at the UCI Health Chao Family Comprehensive Cancer Center (搜索), is leading related clinical research efforts to evaluate new approaches that could improve patient care.