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‘We Never Dared to Think About the Cure’

The Atlantic

www.theatlantic.com › health › archive › 2024 › 11 › lupus-car-t-immune-reset-autoimmune-disease › 680521

Lupus, doctors like to say, affects no two patients the same. The disease causes the immune system to go rogue in a way that can strike virtually any organ in the body, but when and where is maddeningly elusive. One patient might have lesions on the face, likened to wolf bites by the 13th-century physician who gave lupus its name. Another patient might have kidney failure. Another, fluid around the lungs. What doctors can say to every patient, though, is that they will have lupus for the rest of their life. The origins of autoimmune diseases like it are often mysterious, and an immune system that sees the body it inhabits as an enemy will never completely relax. Lupus cannot be cured. No autoimmune disease can be cured.

Two years ago, however, a study came out of Germany that rocked all of these assumptions. Five patients with uncontrolled lupus went into complete remission after undergoing a repurposed cancer treatment called CAR-T-cell therapy, which largely wiped out their rogue immune cells. The first treated patient has had no symptoms for almost four years now. “We never dared to think about the cure for our disease,” says Anca Askanase, a rheumatologist at Columbia University’s medical center who specializes in lupus. But these stunning results—remission in every patient—have fueled a new wave of optimism. More than 40 people with lupus worldwide have now undergone CAR-T-cell therapy, and most have gone into drug-free remission. It is too early to declare any of these patients cured for life, but that now seems within the realm of possibility.

Beyond lupus, doctors hope CAR-T portends a bigger breakthrough against autoimmune diseases, whose prevalence has been on a troubling rise. CAR-T has already been used experimentally to treat patients with other autoimmune diseases, including multiple sclerosis, myositis, and myasthenia gravis. And the success of CAR-T has inspired researchers to borrow other—cheaper and simpler—strategies from cancer therapy to kill immune cells gone awry. Not all of these ideas will pan out, but if any do, the next few years could bring an inflection point in treating some of the most frustrating and intractable diseases of our modern era.

CAR-T-cell therapy was originally developed as a way to kill malignant cells in blood cancer. It could, scientists later reasoned, also be used to kill specific white blood cells, called B cells, that go haywire with certain autoimmune diseases. One group tried a CAR-T-like therapy against an autoimmune disease called pemphigus vulgaris, and another CAR-T against lupus. It worked—but these experiments were only in mice.

This was the sum total of available scientific evidence when a 20-year-old woman came to her doctors in Erlangen, Germany, asking to try anything for her severe and uncontrolled lupus. None of the long-term medications typically used to manage lupus were working. Her kidneys, heart, and lungs were all failing, and she could walk only 30 feet by herself. CAR-T was risky, her doctor agreed, but lupus was killing her.

CAR-T-cell therapy could essentially turn her immune system against itself. First, doctors extracted from her blood a class of immune cells, called T cells, which they then engineered into chimeric antigen receptor T (CAR-T) cells that could recognize and destroy the B cells driving her lupus. CAR-T cells can cause dangerous and overwhelming inflammatory responses in cancer patients, and her doctors did worry that CAR-T could do the same for someone with autoimmune disease, whose immune system is already in overdrive. “We take the T cells out, activate them like crazy, and then shoot those massively overactivated T cells in an activated autoimmune disease. So if you think about it, that's kind of crazy to do that, right?” says Fabian Müller, a hematologist-oncologist at the University Hospital of Erlangen and one of the doctors on the German team that pioneered the treatment. But fortunately, the woman with lupus did not have any serious side effects, nor did any of the other patients the German group has since dosed. They are all living their everyday lives, free of lupus symptoms and medications. The woman who could walk a mere 30 feet now runs five times a week, Müller told me. She’s gone back to school and is considering studying for a master’s in immunology.

Müller and his colleagues believe that CAR-T-cell therapy works by wiping out enough B cells to trigger a “deep reset” of the immune system. CAR-T cells are dogged little assassins; they are able to find and destroy even the B cells hiding deep in the body’s tissues. A patient’s B-cell count eventually recovers, but the new ones no longer erroneously attack the body itself. Cancer patients are sometimes considered “cured” after five years of remission, and the first lupus patient to receive CAR-T is not so far off from that milestone. But the therapy cannot erase the genetic predisposition many patients have for the disease, says Donald Thomas, a rheumatologist in Maryland. Whether remission is actually durable enough to be a “cure” will take time to find out.

Still, these extraordinary results have set off a gold rush among biotech companies eager to solve autoimmune diseases. CAR-T start-ups founded to treat cancer are pivoting to target autoimmune diseases. And large pharmaceutical companies such as Bristol Myers Squibb, AstraZeneca, and Novartis are developing their own therapies. Columbia’s Askanase is now an investigator on five separate trials, all using CAR-T or a similar cellular therapy, and she hears from more companies all the time. There’s so much interest, she told me, “I don’t even know there are enough patients” to test new treatments. About 1.5 million Americans have lupus, but only a minority of them—those sick enough to justify experimental treatment but not so sick that they’ve suffered too much irreversible organ damage—are eligible for trials.

For now, CAR-T for lupus and other autoimmune diseases is pretty much only accessible in the U.S. through clinical trials—which, in effect, means it’s inaccessible to almost all lupus patients. Jonathan Greer, a rheumatologist in Florida, works in a seven-doctor practice that treats hundreds of people with lupus; not a single one has received CAR-T. He doesn’t know of a single center in Florida that is up and running to do these studies, so interested patients would have to travel out of state.

Even if it becomes FDA approved for autoimmune diseases, CAR-T is a long and expensive process. Because each patient’s own cells are reengineered, it cannot be easily scaled up. The cost of CAR-T for cancer runs about $500,000. Patients also need chemotherapy to kill existing T cells to make room for CAR-T, which adds risk, and in lupus, they usually need to taper off any medications keeping their disease in check, which can cause flare-ups. All these complications make the current iteration of CAR-T suitable only for lupus patients with severe disease, who have run out of other options.

The practical limitations of CAR-T have dogged the cancer field for a long time now, and researchers have already come up with ideas to get around it. A number of simpler strategies for killing B cells are now making their way from blood cancer to autoimmune disease. They include using donor T cells, a different type of immune cell called natural killer cells, or a molecule that binds a T cell to the B cell it’s meant to destroy. Those molecules, called bispecific T-cell engagers, or BiTEs, are “cheap, fast, uncomplicated,” Müller said, but they may not penetrate as deeply into the tissues where B cells reside. Nevertheless, in September, The New England Journal of Medicine published two successful case reports describing successful treatment in a handful of autoimmune diseases, including lupus, with a BiTE called teclistamab. Similar BiTES on the market could be repurposed for autoimmune disease too.

These simpler therapies may ultimately be “good enough,” Askanase said. And their ease of use could ultimately beat out custom CAR-T therapy, which is unlikely to reach all of the millions of people with lupus worldwide. It’s simply too expensive and too cumbersome, a problem that has held back other cutting-edge therapies that were approved to much initial fanfare. Even if CAR-T itself is never widely adopted for autoimmune diseases, it has opened the door to new ideas that could one day revolutionize their treatment.