CAR-T cell therapy for myasthenia gravis shows promise in small study by Cartesian Therapeutics

Danny DeBerry was starting to lose hope. For more than a decade, the North Carolina forester had suffered from myasthenia gravis, a disease where a person’s own immune system mistakenly attacks and destroys the vital junctions between nerves and muscles.

What began as double vision problems that left him seeing two of every tree in the woods soon morphed into leg and arm weakness. A couple of years ago, he could barely walk from his house to his pickup truck without having to stop and catch his breath. Just as depression was sinking in, DeBerry read about an experimental treatment called a CAR-T cell therapy that might help him.

Researchers at the University of North Carolina were testing whether immune cells taken from a patient could be programmed to help clear out the source of the pathogenic antibodies that were eroding his muscles. The treatment, developed by biotech startup Cartesian Therapeutics, takes a page from the cancer playbook in which engineered T cells originally designed to treat advanced blood cancers are now being repurposed to treat autoimmune diseases.

Over the course of six weeks early last year, DeBerry got six infusions of the cell therapy. After the third dose, he was back in the woods working. And after the final one, he was outpacing his wife, biking ten miles along the beach — something he could scarcely imagine just months prior. He’ll turn 69 next month. “It’s really changed my life,” he told Endpoints News.

DeBarry’s fate is perhaps the most dramatic among 14 patients who got the therapy in an early-stage study, which was published in Lancet Neurology on Thursday. The study was focused on proving the safety of the repeatedly administered treatment but also found promising, albeit early, glimpses of its potential effectiveness.

Patients who got weekly infusions showed marked and sustained improvement on multiple clinical scales — changes roughly two or three times above the threshold for being clinically meaningful — over a median 6-month follow-up. Two patients were able to stop getting the grueling antibody infusions that were keeping their disease at bay, and three others had almost no measurable symptoms at the most recent check-in.

Murat Kalayoǧlu

“It seems like there’s not only a deep response, but a very durable response,” Cartesian CEO Murat Kalayoǧlu said in an interview with Endpoints News. “These are massive improvements in the quality of life for these patients.”

James Howard, one of the paper’s authors and DeBarry’s doctor at UNC cautioned against making “any broad generalizations” about the promise of CAR-T for myasthenia gravis since the study was small and no one got a placebo, but he’s excited to see how it works in larger trials.

“There’s enough of a signal to give us a lot of hope that we can move forward with this,” he said. “I’m also very impressed by the lack of significant adverse events.”

Cartesian started a bigger study earlier this year. Results of that Phase IIb trial pitting the therapy against a placebo in 30 people could come in the first half of next year, followed by a Phase III study as soon as mid-2024, Kalayoǧlu said.

Safer therapies through RNA

In recent years, numerous biotech companies, including Cabaletta Bio, Capstan Therapeutics, and Kyverna Therapeutics, have collectively raised hundreds of millions of dollars to unleash CAR-T cells on autoimmune diseases, and pharma giant Novartis plans to test a CAR-T therapy for lupus.

James Howard

The therapies target destruction of rogue immune cells that wreak havoc on a person’s body. Cartesian’s treatment, Descartes-08, is one of the most advanced in the field. It goes after a marker called BCMA found on plasma cells — a white blood cell that pumps out antibodies, including the harmful ones that attack neuromuscular junctions in myasthenia gravis.

“The idea is to eliminate the very source that is producing the pathogenic autoantibodies responsible for autoimmune diseases,” Kalayoǧlu said. “We hope that could have a dramatic impact.”

Many CAR-T therapies permanently alter the DNA of the new T cells. To make room for those engineered cells, patients typically get chemotherapy to clear out their old white blood cells. Once in the body, the engineered cells divide and their progeny continue to hunt down cancer cells that reemerge.

While that multiplying effect is helpful for treating leukemia and lymphoma, some experts believe it’s responsible for the dangerous and sometimes deadly immune reaction known as cytokine release syndrome that plagues CAR-T developers.

“In newly diagnosed cancers or in autoimmune diseases, that kind of toxicity is just not something that people are going to tolerate,” Kalayoǧlu said. Cartesian is among a growing number of companies betting that a more temporary alteration of T cells, made with short-lived messenger RNA rather than DNA, will lower the risks.

Encouraging signs of efficacy

The Gaithersburg, MD-based company of about 30 people has kept a low profile since its 2016 founding. The private firm Schooner Capital has made a “significant” investment in the startup, but neither company would divulge exactly how much. Cartesian has also won more than $6 million in grants from the National Institutes of Health, which Kalayoǧlu calls a “relatively small portion” of its total funding.

To make the therapy, Cartesian first collected white blood cells from patients, isolated the killer T cells in its Maryland lab, coaxed them to multiply, and then gave them mRNA encoding a chimeric antigen receptor (CAR) protein that targets BCMA. The cells are split into doses, frozen, and shipped back to the hospital, where patients got six infusions, either twice a week, weekly, or monthly.

While the treatment appeared both robust and durable in the 7 patients who got weekly doses, the monthly dose didn’t seem to be effective, and the benefits from the biweekly therapy were shorter-lived.

Jonathan Epstein

“In terms of efficacy, we can say very little, but there are some encouraging signs,” said Jonathan Epstein, a researcher from the University of Pennsylvania who is working on CAR-T therapies for fibrotic diseases and is cofounder of Capstan Therapeutics, which is also developing mRNA-engineered cell therapies for autoimmune diseases and cancer.

In Cartesian’s Phase 1b/2a study, headache, nausea, vomiting, and fever were the most common side effects. Crucially, researchers didn’t spot signs of cytokine release syndrome, and the treatment doesn’t require pre-conditioning with chemotherapy.

Two patients withdrew before finishing all six infusions, one due to severe hives that were “possibly related” to the therapy and the other for “personal reasons,” according to the Lancet paper. Another with a history of hypertension and high cholesterol had a heart attack 3 days after his final infusion, which was deemed unrelated to the therapy.

The levels of antibodies that attack the neuromuscular junction fell by 22% after 8 weeks, and the total level of all IgG antibodies — including ones important for fighting infections — dropped by 18% after 12 weeks. Those modest changes have researchers wondering if some other mechanism, possibly involving changes to a person’s repertoire of T cells, is at play.

“We’re looking into that, but the mechanism of this disease is quite complicated,” Kalayoǧlu said. “We don’t yet know exactly how Descartes-08 is benefiting patients.”

UPenn’s Epstein also said it wasn’t entirely clear why the therapy might be working. “There’s some possibility that the immune system is being reset by the treatment,” he said.

That mystery isn’t stopping the company from moving ahead, and Kalayoǧlu said the company will talk about its plans for other autoimmune diseases toward the end of the year.

And more than a year after DeBerry’s final infusion, his doctor says he is still in remission. He’s hopeful that if his condition flares up, he could get the therapy again.

“I am still maxing out on all their tests. I don’t have any double vision. And my leg and arm strength is good,” he said. “I was just so lucky and blessed to have found this.”

therapeutics
antibodies
cell therapy
biotech
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