Rheumatology — the study of immune-system-driven diseases of the bones, joints, muscles, and in-betweens — has inherited plenty of hand-me-downs from cancer research. For example, there are ways of squelching an immune system in order to shrink certain kinds of cancerous tumors. And scientists have found that, when retrofitted, those strategies can also alleviate some symptoms of autoimmune conditions.
CAR-T therapy, a way of amplifying a person’s own immune power against a disease target, is the latest tool in this shared playbook. Half a dozen people with severe lupus have gone into remission from their disease after receiving CAR-T, a result that researchers say could usher in a new era for a whole suite of hard-to-treat autoimmune conditions.
In lupus, an array of immune system agents rush to attack what the cellular receptors have flagged as a suspect pathogen, but what they’re actually pursuing is the body’s own proteins. As B cells show up to the fight, the body creates antibodies against itself, kickstarting a vicious cycle of inflammation and immune attacks that can lead to organ damage, pain, fatigue, and other symptoms.
CAR-T works by modifying some T cells involved in immune system functions, and turning them into rovers that can hunt the body for a certain target. In the case of lupus, the T cells were set on the trail of CD19, a protein on the surface of the B cells involved in disease flare-ups.
The Centers for Disease Control and Prevention estimates about 200,000 adults in the United States have common lupus, called systemic lupus erythematosus. Women account for a vast majority of these cases. Black girls and women and Latinas are at the highest risk of developing the disease, for unknown reasons.
Researchers suspect lupus is partly genetic and partly environmental (some trigger sets it off), but there’s no agreed-upon cause of lupus, which makes it a difficult disease to study and “very challenging to treat, particularly in a disease that predominantly affects women of child-bearing age who understandably wish to avoid exposure to potentially toxic medications,” said PJ Utz, a professor of medicine at Stanford University who runs a research lab that studies autoimmunity. Many lupus patients are treated with multiple drugs, including intense steroids, in an attempt to control the disease.
More than 100 autoantibodies have been identified in lupus patients. The latest research from Georg Schett and his colleagues at Friedrich Alexander University Erlangen-Nuremberg showed CAR-T was able to rid five lupus patients of autoantibodies linked to the disease — essentially granting the patients a new immune system. The work, published on Thursday in Nature Medicine, builds on research Schett and his team published a year ago, showing one woman went into remission from her severe lupus after being treated with CAR-T. The innovative therapy, which is in such high demand it’s causing quandaries for oncologists, was used on these lupus patients with a “compassionate use” authorization, a permission slip that lets researchers try unapproved drugs on severely ill patients with no other treatment options.
Other B-cell blockers and depletion therapies, like those immunosuppressive drugs, can get rid of misbehaving B cells in the blood, but often fail to penetrate other tissues, such as the lymph nodes and bone marrow; CAR-T goes deeper, clearing out B cells throughout the body.
One lupus patient, who got CAR-T about 18 months ago and hasn’t received any therapies since, has remained free of disease symptoms, Schett said. A second patient has been in drug-free remission for a year. It’s too early to say the patients are cured, but results are encouraging, even to Schett. It seems “miraculous” to him that CAR-T could help disentangle and resolve cases of severe lupus. “We were really surprised how effective it was,” he said. “I have to say that blew us away.”
One hundred days after the initial CAR-T treatment, the B-cells reappeared, causing the oncologists on the research team to worry that lupus flare-ups would start again. But they didn’t. The new B-cells acted normally, performing their immune system functions without exaggeration, and the autoantibodies haven’t returned. This suggests that “pathological B cells producing the damaging antibodies are not long-lived cells in the bone marrow, but are instead in inflamed tissues,” and laden with CD19 surface proteins, said Carola Vinuesa, an autoimmunity researcher at the Francis Crick Institute in London who was not involved with the research.
Beyond that, immune system function wasn’t destroyed, as it often is in cancer patients who undergo CAR-T (other cancer treatments, such as chemotherapy, make patients deeply immunocompromised before they even start CAR-T). Instead, the therapy got rid of lupus-causing antibodies while preserving immunity to pathogens that the patients had been vaccinated against, such as measles, mumps, rubella, varicella and hepatitis B. The researchers did not report any serious infections or toxic effects in the five patients, either.
“This would seem to be the holy grail of treatment,” said Mark Leick, a physician at the Hematopoietic Cell Transplant and Cell Therapy Program at Massachusetts General Hospital.
A few months ago, Schett and his colleagues followed up with their six patients. The first patient was a woman who had dropped out of school because her lupus was so severe it caused her heart muscle to swell. As of July, she was back in classes. Another patient started riding horses again, and another is DJing in nightclubs. Before CAR-T led them to remission, disease controlled their plans, dominated their conversations, they told Schett. Chronic fatigue, now gone, was among the most draining symptoms of their lupus. Now they are rediscovering their lives. “It’s pretty touching that you change the life of a young person,” Schett told STAT.
The possibilities start at lupus, but extend to a variety of other diseases that involve B cells, such as systemic sclerosis, multiple sclerosis, and severe autoimmune conditions. There’s tremendous need: One of the best-selling drugs in the world, Humira, is a treatment for Crohn’s disease, plaque psoriasis, rheumatoid arthritis, and other such conditions. If the effects of CAR-T on lupus patients can be extrapolated to other autoimmune conditions, “that’s a complete game-changer,” said Leick, who is part of the CAR-T-developing Maus Lab at Mass. General.
And, if the toxicity and other health risks are low, that means the therapy could be performed in an outpatient setting one day, giving many more patients access to treatment, whether it be in a rural doctor’s office or another country. That’s the best-case scenario. Currently, CAR-T is an expensive therapy — costing around $400,000 — and labor-intensive to make, since it is personalized to each patient. The U.S. Food and Drug Administration has approved just a handful of CAR-T products for certain cancers. Until the agency approves more, drugmakers are scrambling to keep up with demand. Similar issues could limit the availability of CAR-T for autoimmune conditions, even if it were to be approved.
In order to get there, researchers will first need to replicate the findings in larger groups and clinical studies, and make sure CAR-T is truly safe and effective across the board.
This article was supported by a grant from Bloomberg Philanthropies.
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