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NEJM paper fills in details on ‘remarkable’ CAR-T result in autoimmune disease

A new research paper offers the most thorough look yet at a study that sparked the drug industry’s recent experimentation with cell therapy for autoimmune diseases.

The paper, which was published in The New England Journal of Medicine on Wednesday, comes from a team of scientists at the Friedrich Alexander University, Erlangen-Nurnberg in Germany. They detail how 15 people with severe autoimmune conditions experienced either disease remission or a sharp reduction in symptoms after an infusion of a kind of cell therapy known as CAR-T. 

The patients, who had tough-to-treat forms of lupus, inflammatory myositis or systemic sclerosis, have since been followed for a median of 15 months. None have needed medications they typically used to manage their conditions, and all treatment-related side effects were judged by investigators to be mild or moderate. 

The results were presented at a medical meeting in December, but the NEJM paper gives fuller detail of the study findings.

“The findings are remarkable,” wrote John Isaacs, a professor of clinical rheumatology at Newcastle University, in an editorial also published Wednesday. Isaacs wasn’t involved in the study.

The paper adds to research suggesting CAR-T therapy, a method of engineering immune cells to fight cancer, might be applied to autoimmune disease. The idea is that CAR-T treatments, rather than destroying tumors, could eliminate the antibody-producing B cells that have malfunctioned in many autoimmune disorders. 

Though the study in Germany is small and lacks a placebo control, its results have already influenced a wide range of drugmakers. Since 2022, biotechnology and pharmaceutical firms have begun about a dozen clinical trials testing cell therapies in lupus. At least six others have received Food and Drug Administration clearance to begin testing. 

Drugmakers are also evaluating CAR-T therapies in other autoimmune conditions like myasthenia gravis and multiple sclerosis.

“There’s a huge potential for patients to really benefit,” said Samit Hirawat, chief medical officer of Bristol Myers Squibb, one of the companies developing a CAR-T treatment for autoimmune disease, in a recent interview. 

The new NEJM results highlight the approach’s promise, as well as the questions developers will have to answer in testing. 

The study suggests CAR-T may induce a “reset” of patients’ autoimmune disease. In the months following treatment, participants’ B cell networks were reconstituted, and the number of destructive “autoantibodies” associated with inflammatory disease diminished. Participants have gone up to two years after their B cells were replenished without signs of a relapse. Other markers of disease have also disappeared. 

“Even though it is premature to judge whether these patients are indeed cured from their autoimmune disease … CAR T cells at least appear to be able to achieve sustained disease- and drug-free remission,” the study authors wrote. 

However, due to the trial’s small size and scope, it’s unclear how long the benefits from treatment will last, whether people might need to be retreated, or if any long-term health issues arise.

When used in cancer, for example, CAR-T has in rare cases been associated with secondary malignancies

Published research has also linked depleted B cell counts to poor health outcomes from COVID-19, Isaacs noted. Multiple study participants contracted COVID-19 after therapy in the autoimmune disease study.

The reduction — but not elimination — of some protective and vaccine-related antibodies raise the question of whether people will need new shots, the authors wrote. 

Additionally, developers must figure out the best chemotherapy “conditioning” regimen to prepare patients for treatment. Investigators in the German study used a pair of drugs that are typically administered before CAR-T therapies. But they noted how the field will need to determine “whether and what doses are needed” in an autoimmune disease setting, where the expectations for a drug’s safety profile are different than with deadly cancers.

If those problems can be solved and “extended follow-up reinforces the current data, the benefit-to-risk ratio is likely to prove acceptable to both physician and patient, at least in certain cases of refractory disease,” Isaacs wrote. 

“Nonetheless,” he cautioned, “such therapy is in its early days, and there remains much to observe and understand.”