CAR T-Cell Therapy Shows Early Promise in Progressive Multiple Sclerosis: First Patients Treated in Pioneering Trials
核心洞察
Grace Miller became the first patient at Cleveland Clinic to receive CAR T-cell therapy for progressive MS in March 2025, reporting gradual but constant improvements in mobility and vision.
Beth Smith became the third person worldwide to undergo allogeneic CAR T-cell therapy for MS at UNMC, experiencing noticeable functional gains including restored toe-tapping ability.
CAR T-cell therapy aims to target and eliminate disease-causing B cells (搜索) in tissues including the nervous system, potentially allowing the immune system to reset and halt MS progression.
Two pioneering clinical trials at major U.S. academic medical centers are exploring whether CAR T-cell therapy — a treatment already approved for certain blood cancers — can alter the trajectory of progressive multiple sclerosis (搜索), a form of the disease where symptoms steadily worsen and current medications offer limited efficacy.
Grace Miller, a 45-year-old mother and attorney from central Indiana, became the first patient at Cleveland Clinic and among the first in the country to receive CAR T-cell therapy for MS in March 2025. Separately, at the University of Nebraska Medical Center (UNMC), Beth Smith became the third person in the world to undergo a first-of-its-kind allogeneic CAR T-cell therapy trial for the same disease.
A Disease with Unmet Need
Miller was diagnosed with MS in 2005 at age 24, after experiencing fatigue, numbness, vertigo, and near-total vision loss. For years, medication kept her symptoms manageable — she completed law school, ran multiple half marathons, and raised two children. But her condition gradually progressed, and by 2021 she was walking with a cane.
"Grace has progressive MS, a form of the disease where symptoms steadily worsen over time. While we've made great progress in MS treatment overall, current medications are not as consistently effective for progressive MS," said Jeffrey Cohen, MD, a Cleveland Clinic neurologist.
How CAR T-Cell Therapy Works in MS
In multiple sclerosis (搜索), the immune system mistakenly attacks myelin, the protective layer around nerves. CAR T-cell therapy aims to target specific immune cells called B cells (搜索) that drive this damage.
"Unlike other treatments that only go after B cells (搜索) in the blood, CAR T-cell therapy goes a step further by also targeting and eliminating those disease-causing cells in the tissues, including within the nervous system," Dr. Cohen explained. "By removing these cells, the hope is the immune system can recover and reset — potentially leading to immediate and sustained control of autoimmune diseases like MS."
At Cleveland Clinic, Miller's treatment process began with collection of her own T cells, which were then genetically reprogrammed in a laboratory to target disease-causing B cells (搜索). Before the modified cells were infused back into her body, she underwent a short course of chemotherapy to create space in her immune system for the new CAR T cells.
At UNMC, Smith's trial used an allogeneic approach, in which T cells from a healthy donor are genetically modified to target and destroy the harmful immune cells driving autoimmune disease. The trial was led by Lakshman Narain Arcot Jayagopal, MBBS, MD, assistant professor in the UNMC Department of Neurological Sciences, with support from the Gene and Cellular Support Service led by Matthew Lunning, DO, medical director of the Gene and Cellular Therapy Program.
Early Signs of Improvement
Following her CAR T-cell infusion, Miller reported gradual, measured improvements. Before treatment, her legs would shake uncontrollably when she stood; afterward, she could stand without shaking. While she still occasionally uses a cane as she works to rebuild neural pathways, she can walk longer distances. Her nystagmus-related eye symptoms have also improved, enabling her to drive farther.
"I was even able to hold my friend's little girl in my arms for the first time. Before, I thought this wasn't safe because I didn't feel strong enough," Miller said. "These may seem like small milestones, but for me, they've been life-changing. The improvements have been gradual but constant."
Smith has experienced similarly tangible changes. Since receiving her infusion, she can tap her toes on both feet — something she could not do before. She demonstrated the change for Dr. Lunning during a follow-up visit. "I was sitting in my wheelchair, and Dr. Lunning came in and hopped up on the exam table. I tapped my toes, and he said, 'Beth, can I record your toe tapping?' And I said, 'Absolutely,'" Smith recalled.
The Science of Recovery
Dr. Cohen emphasized that the body naturally attempts to repair MS-related damage, but the disease often progresses faster than those repair mechanisms can keep up. After CAR T-cell therapy, the hope is that halting further immune-mediated damage gives the body time to heal.
"We know the body naturally tries to compensate for damage, either by repairing the affected nerves or by allowing other ones to take over those functions. That ability is called neuroplasticity, and there's growing evidence physical therapy can help promote it," Dr. Cohen said. "The goal is to stop the ongoing damage as effectively as we can and then support the body's natural ability to repair itself."
Cautious Optimism and Next Steps
Both trials remain in early phases, and researchers stress that many unknowns persist. CAR T-cell therapy for MS carries possible risks and side effects, and it is still being determined whether it represents a viable treatment and which patients might benefit most.
"Although we're still early in understanding whether CAR T-cell therapy can be effective for MS, the initial results have been encouraging," Dr. Cohen said. "They reflect increasing interest in applying this therapy to progressive forms of the disease."
At UNMC, philanthropic support has been instrumental in advancing the research. The Aidan O'Neil Foundation recently transferred $4.2 million in assets to the University of Nebraska Foundation, creating two endowed chairs and establishing the Aidan O'Neil Gene and Cellular Therapy Research Fund to support CAR T-cell therapy infrastructure and research capabilities.
For the patients involved, the trials represent something that previously seemed impossible. "I'm looking forward to hopefully continuing to get better. Even having the chance to potentially improve my condition didn't seem possible before this treatment," Miller said. "I'm excited to have been one of the first to have CAR T-cell therapy for MS, and I'm hopeful it can help others down the road."