Potential treatment for a rare autoimmune disorder adapted from CAR-T therapy

Press release

Thursday, June 22, 2023

First step of NIH-supported trial in developing a new approach to treat myasthenia gravis.

Evidence from a small clinical trial suggests that a variation of the advanced blood cancer immunotherapy known as CAR-T could be adapted to treat Myasthenia gravis, an autoimmune disorder of the nervous system. Modified CAR-T, short for chimeric antigen receptor T cells, therapy being used by scientists offers the potential for a more lasting reduction in Myasthenia gravis symptoms and was well tolerated without significant adverse effects. The study, published in The Lancet Neurologywas supported by a small business grant from the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health, and sponsored by Cartesian Therapeutics, Gaithersburg, Maryland.

“Repurposing an innovative therapy like CAR-T to potentially treat a neurological disorder shows the versatility of immunotherapies in cases where treatment options are limited or nonexistent,” said Emily Caporello, Ph.D., director of the Small NINDS Companies.

Myasthenia gravis is a chronic autoimmune disorder most often caused when the body’s immune system attacks a protein found where nerve cells communicate with muscles. The disease is characterized by muscle weakness that worsens after periods of activity and may improve somewhat after rest. Current treatments focus on controlling symptoms, mainly muscle weakness.

In the study, 14 people with generalized myasthenia gravis received varying doses of a modified form of CAR-T therapy, known as Descartes-08, which targets cells responsible for producing antibodies that cause myasthenia gravis. The ideal dose was determined to be once a week for six weeks. The first data on the effectiveness of the treatment are promising, but additional clinical studies are needed to evaluate the efficacy of the therapy. Three patients who received Descartes-08 showed complete or near complete clearance of their symptoms, which continued six months after treatment. Two others no longer required chronic treatment with intravenous immunoglobulin, which is currently used in some cases of severe MG.

“What we saw were profound and long-lasting responses to Decartes-08 that persisted for at least six months after treatment,” said Murat V. Kalayoglu, MD, Ph.D., president and CEO of Cartesian Therapeutics. “We have now begun a larger randomized placebo-controlled study, which is the first of its kind for an adoptively designed cell therapy.”

CAR-T therapy involves taking a patient’s T cells, a key part of the immune system that can recognize and destroy invading pathogens, and reprogramming them to attack a specific target. In the case of blood cancers, the new target is the cancer itself. For myasthenia gravis, the target is the corrupted cells that produce the harmful antibodies.

Many immunotherapies, including CAR-T, carry the risk of serious side effects that, while tolerable in advanced cancers, prohibit their use in more chronic conditions such as myasthenia gravis. Normally, T cells are reprogrammed with DNA, which persists within cells and is copied each time cells divide. This can lead to an amplified effect and serious side effects.

To avoid this side effect, Descartes-08 uses messenger RNA (mRNA), which is not duplicated when cells divide, instead of DNA to reprogram T cells. The result is a short course of treatment that is administered multiple times in instead of the single-dose regimen typically used in DNA-programmed CAR-T therapy. The primary objective of this trial was to determine the ideal dose of Descartes-08 that would effectively reduce symptoms of muscle weakness with minimal side effects.

The Descartes-08 therapy is now being tested in a larger clinical trial to determine its ability to reduce the symptoms of myasthenia gravis. Importantly, this trial will also include a placebo group, which is an important control to confirm that any observed improvement is due to treatment and not unrelated effects.

This trial was supported by a grant from the NINDS Small Business Program (NS115426-01A1), which is designed to encourage research and development that may lead to commercial therapeutics. The clinical trial reported in this study and the ongoing Phase 2 trial are registered with ClinicalTrials.gov (NCT04146051).

About the National Institute of Neurological Disorders and Stroke (NINDS): CHILDREN is the nation’s leading funder of brain and nervous system research. The NINDS mission is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH):NIH, the nation’s medical research agency, includes 27 institutes and centers and is a component of the US Department of Health and Human Services. NIH is the lead Federal agency conducting and supporting basic, clinical, and translational medical research , and is researching the causes, treatments, and cures for common and rare diseases. To learn more about the NIH and its programs, visit www.nih.gov.

NIH…turning discovery into health^®

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