Landmark study marks first successful use of RNA cell therapy for an autoimmune disease

UCI conducted trial of novel therapy modifying patients’ T-cells with mRNA to treat myasthenia gravis and other autoimmune diseases

UCI Health neurologist Dr. Tahseen Mozaffar is a co-author of the paper and the trial’s principal investigator at UCI.

A landmark paper published today in The Lancet Neurology describes marked and long-lasting clinical improvement in patients who were treated with Descartes-08, a cutting-edge RNA CAR-T (rCAR-T) therapy for the debilitating autoimmune neurological disease myasthenia gravis (MG). This is the first clinical trial using rCAR-T to treat autoimmunity, and the first successful Phase 2 trial using an engineered cell therapy to treat autoimmunity. Descartes-08 was developed by Cartesian Therapeutics, a clinical-stage biotechnology company investigating cell therapies for autoimmune diseases. UCI Health and the UCI Alpha Clinic were among several clinical sites in the U.S. to enroll patients.

“Conventional, DNA-engineered CAR T-cells are highly effective in treating several blood cancers, but associated toxicities and the need for lymphodepletion chemotherapy limit their use beyond oncology,” said Dr. Miloš Miljković, chief medical officer at Cartesian. “To expand the capabilities of cell therapy to new areas and improve safety, we engineered CAR T-cells with RNA and used them to treat patients with MG.”

The study enrolled 14 patients with generalized MG. Patients receive six infusions of rCAR-T therapy, administered as an outpatient treatment, without lymphodepletion. Patients were followed for a median duration of six months (range: three–nine months). rCAR-T was well tolerated, with no dose-limiting toxicities, cytokine release syndrome, or neurotoxicity. Clinical improvements were marked and long-lasting across four validated MG disease scoring systems. Strikingly, at six months, the average improvements were about three-fold greater than thresholds considered clinically meaningful. Clinical benefit was sustained long-term for most patients, even months after completing the course of therapy. Three patients achieved complete or near-complete eradication of all disease symptoms; two other patients who relied on chronic IVIg therapy prior to enrollment ceased to need this therapy after Descartes-08 treatment.

“There is no known cure for generalized myasthenia gravis,” said Dr. Tahseen Mozaffar, a UCI Health neurologist, co-author of the paper and the trial’s principal investigator at UCI. “While other treatments offer some short-term relief, determining whether mRNA-modified cell therapies can be safely and cost-effectively used to treat autoimmune diseases like generalized myasthenia gravis offers patients the possibility of a long-term treatment.”

The results described in The Lancet Neurology suggest that rCAR-T may be useful in treating a variety of other autoimmune diseases and may overcome many of the risks and toxicities associated with conventional DNA-based CAR-T cells.

“Currently, the mainstay of myasthenia therapy is chronic use of broad immunosuppression, which has many drawbacks,” said Dr. James Howard, professor of neurology at University of North Carolina – Chapel Hill and a senior author on the paper. “The prospect of inducing potent, durable responses and reducing or eliminating use of immunosuppressive therapy is very appealing to the myasthenia community. Based on the compelling results of this paper, we are now enrolling patients with MG into a randomized placebo-controlled study, the first study of its kind for an engineered adoptive cell therapy.”

“We are grateful to our community of MG patients and physicians for enabling clinical development of novel therapeutics such as rCAR-T,” said Samantha Masterson, President & CEO of Myasthenia Gravis Foundation of America. “A safe, personalized therapy with durable clinical benefit would be a welcome addition to the growing toolkit of MG treatments.”

The full paper, “Safety and Efficacy of Autologous RNA Chimeric Antigen Receptor T-cell (rCAR-T) Therapy in Myasthenia Gravis: a prospective, multicenter, open-label, non-randomized phase 1b/2a study,” is available online, along with an accompanying commentary on the paper by Dr. Andreas Mansel, professor of neurology at the NeuroCure Clinical Research Center in Berlin.

In addition to co-senior authors Howard and Mozaffar, the paper’s other co-authors are Drs. Volkan Granit and Michael Benatar of University of Miami (co-first authors), Dr. Nizar Chahin of Oregon Health and Science University, Dr. Gregory Sahagian of Neurology Center of Southern California, Dr. Marc Feinberg of SFM Research – Boca Raton, Dr. Adam Slansky of Neurology Associates – Orlando, Dr. Tuan Vu of University of South Florida, and other members of the MG-001 Study Team. The study was funded in part by the National Institutes of Health (NIH) with a grant from the National Institute of Neurological Disorders and Stroke (NINDS grant NS115426).

About MG

Myasthenia gravis (MG) is a chronic autoimmune disorder that causes disabling muscle weakness and fatigue. For most people with MG, the disease is characterized by the presence of antibodies against the acetylcholine receptor, a protein found on the surface of nerve cells that plays a key role in muscle contraction. There is currently no cure for MG, and treatment typically requires chronic immunosuppressive medicines, with their attendant risks and side effects.

About Descartes-08 and Cartesian Therapeutics

Descartes-08 is a first-in-class rCAR-T in clinical development for MG and other autoimmune diseases. Compared to conventional DNA-based CAR T-cell therapies, rCAR-T does not require lymphodepletion chemotherapy, has predictable and controllable pharmacokinetics, and avoids the risk of genomic integration. These attributes are expected to make Descartes-08 safer than DNA-based cell therapies. Descartes-08 is a personalized (autologous) therapy during which cells are collected, engineered with RNA, and returned to the same individual in an outpatient setting. A course of therapy consists of six weekly infusions. For more information about enrolling into the Phase 2b trial, visit cartformg.org.

For more information visit cartesiantherapeutics.com.

About UCI Health

UCI Health is the clinical enterprise of the University of California, Irvine, and the only academic health system in Orange County. Patients can access UCI Health at primary and specialty care offices across Orange County and at its main campus, UCI Medical Center in Orange, Calif. The 459-bed, acute care hospital, listed among America’s Best Hospitals by U.S. News & World Report for 21 consecutive years, provides tertiary and quaternary care, ambulatory and specialty medical clinics, behavioral health and rehabilitation services. UCI Medical Center is home to Orange County’s only National Cancer Institute-designated comprehensive cancer center, high-risk perinatal/neonatal program and American College of Surgeons-verified Level I adult and Level II pediatric trauma center and regional burn center. UCI Health serves a region of nearly 4 million people in Orange County, western Riverside County and southeast Los Angeles County. Follow us on Facebook, Instagram, LinkedIn and Twitter.