Cell-killing cancer therapy shows promise for a devastating autoimmune disorder | Science

Opening a new frontier in fighting autoimmune disease, researchers have successfully treated five lupus patients with a novel cell therapy that turns run-of-the-mill immune cells into specialized hunters of rogue cells helping fuel illness. The patients treated with the new therapy all saw their severe symptoms, including kidney and other organ dysfunction, largely disappear.

The results “are phenomenal,” says Betty Diamond, an immunologist and rheumatologist at the Feinstein Institutes for Medical Research who cares for lupus patients and was not involved in the work. Despite her excitement, she cautions that the approach needs to be tried in many more people with lupus to prove it’s safe and has lasting benefits.

The treatment, called chimeric antigen receptor T cell (CAR-T) therapy, involves isolating T cells—sentries of the immune system—from a patient’s blood and genetically modifying them to seek and destroy other cells that are causing disease. The engineered T cells are then reinfused into the patient. CAR-T therapy was first developed more than a decade ago to treat certain leukemias and lymphomas. In those conditions, the modified T cells target another type of immune cell, B cells, that have turned cancerous. But in lupus, B cells go awry in a different way, making antibodies that attack a person’s own tissue. People with lupus can suffer from kidney failure, heart and lung problems, joint pain, and other complications. The disease is notoriously difficult to treat.

Researchers have long eyed CAR-T therapy as a potential strategy for tackling autoimmune conditions, but there have been concerns, too. T cells churn out molecules called cytokines which can lead to inflammation—a complication not uncommon in cancer patients who get CAR-T therapy. In people with autoimmune diseases, cytokines can help drive their symptoms, so some researchers worried the therapy might worsen disease rather than ease it.

Then last year, a team led by Georg Schett, an immunologist and physician at the University of Erlangen-Nürnberg, reported in The New England Journal of Medicine that a 20-year-old woman with lupus went into remission after CAR-T therapy, without serious side effects. “This patient responded really well, safety was really good,” Schett says. “That pushed us to say, ‘This is a way to move forward.’”

He and his colleagues decided to test CAR-T therapy on more lupus patients. They identified three women and a man, all between the ages of 18 and 24, who had organ complications and hadn’t been helped by multiple medications. The strategy Schett embraced is very similar to what physicians have offered people with blood cancers. Before getting CAR-T cells, the lupus patients received chemotherapy to wipe out immune cells, in hopes of giving the transplanted cells more room to multiply and preventing preexisting immune cells from squelching them. All five received CAR-T therapy at Schett’s hospital between 4 months and 18 months ago, and all of them—along with a sixth patient to whom Schett has since administered the treatment—are in remission.

“They really have a different life” now, Schett says. One is horseback riding; another, a disc jockey, “plays in the clubs again,” he notes. A third was able to return to school. Still, Schett cautions that he can’t yet say these young people are cured of their disease; it will take more time to assess whether that’s the case, as the risk of relapse remains.

Schett is also fascinated by what he observed in the patients’ blood after treatment. B cells were initially erased, as was the goal. In the months that followed, new B cells were gradually born—and yet lupus remained at bay, as Schett and his colleagues report today in Nature Medicine. “You’re resetting somehow,” he says, with a clean slate of B cells that isn’t spurring autoimmune attacks.

It’s “a landmark study in the treatment of autoimmunity,” says Aimee Payne, a dermatologist and immunologist at the University of Pennsylvania who has studied a different version of CAR-T therapy for another autoimmune disease, a dangerous blistering skin condition called pemphigus vulgaris. After initial studies in mice, Payne is now involved in a clinical trial sponsored by a company she co-founded, Cabaletta Bio, that has shared results on 15 patients so far. Some patients experienced a temporary improvement in symptoms, and that therapy is gentler—the first 15 didn’t get chemotherapy before receiving their T cells (a subsequent cohort will get a reduced chemotherapy regimen), and the cells are modified to wipe out only a subset of B cells. To Payne, one of the most startling findings in Schett’s study was that the intensive therapy appeared safe for those five patients. “This did not flare disease,” she says. “That’s stunning.”

Schett now wants to try CAR-T therapy in more lupus patients, as well as some with other autoimmune conditions. Recently he treated one patient with scleroderma and another with myositis. Early next year, he plans to launch a clinical trial with 24 additional patients who have either lupus or one of these conditions. Durability of treatment will be key, because CAR-T therapy isn’t a treatment that’s designed for repeated use because of its potential risks and high cost. “If you can stay 3 years or longer in drug-free remission,” he says, “it’s a pretty great story.”

Opening a new frontier in fighting autoimmune disease, researchers have successfully treated five lupus patients with a novel cell therapy that turns run-of-the-mill immune cells into specialized hunters of rogue cells helping fuel illness. The patients treated with the new therapy all saw their severe symptoms, including kidney and other organ dysfunction, largely disappear.

The results “are phenomenal,” says Betty Diamond, an immunologist and rheumatologist at the Feinstein Institutes for Medical Research who cares for lupus patients and was not involved in the work. Despite her excitement, she cautions that the approach needs to be tried in many more people with lupus to prove it’s safe and has lasting benefits.

The treatment, called chimeric antigen receptor T cell (CAR-T) therapy, involves isolating T cells—sentries of the immune system—from a patient’s blood and genetically modifying them to seek and destroy other cells that are causing disease. The engineered T cells are then reinfused into the patient. CAR-T therapy was first developed more than a decade ago to treat certain leukemias and lymphomas. In those conditions, the modified T cells target another type of immune cell, B cells, that have turned cancerous. But in lupus, B cells go awry in a different way, making antibodies that attack a person’s own tissue. People with lupus can suffer from kidney failure, heart and lung problems, joint pain, and other complications. The disease is notoriously difficult to treat.

Researchers have long eyed CAR-T therapy as a potential strategy for tackling autoimmune conditions, but there have been concerns, too. T cells churn out molecules called cytokines which can lead to inflammation—a complication not uncommon in cancer patients who get CAR-T therapy. In people with autoimmune diseases, cytokines can help drive their symptoms, so some researchers worried the therapy might worsen disease rather than ease it.

Then last year, a team led by Georg Schett, an immunologist and physician at the University of Erlangen-Nürnberg, reported in The New England Journal of Medicine that a 20-year-old woman with lupus went into remission after CAR-T therapy, without serious side effects. “This patient responded really well, safety was really good,” Schett says. “That pushed us to say, ‘This is a way to move forward.’”

He and his colleagues decided to test CAR-T therapy on more lupus patients. They identified three women and a man, all between the ages of 18 and 24, who had organ complications and hadn’t been helped by multiple medications. The strategy Schett embraced is very similar to what physicians have offered people with blood cancers. Before getting CAR-T cells, the lupus patients received chemotherapy to wipe out immune cells, in hopes of giving the transplanted cells more room to multiply and preventing preexisting immune cells from squelching them. All five received CAR-T therapy at Schett’s hospital between 4 months and 18 months ago, and all of them—along with a sixth patient to whom Schett has since administered the treatment—are in remission.

“They really have a different life” now, Schett says. One is horseback riding; another, a disc jockey, “plays in the clubs again,” he notes. A third was able to return to school. Still, Schett cautions that he can’t yet say these young people are cured of their disease; it will take more time to assess whether that’s the case, as the risk of relapse remains.

Schett is also fascinated by what he observed in the patients’ blood after treatment. B cells were initially erased, as was the goal. In the months that followed, new B cells were gradually born—and yet lupus remained at bay, as Schett and his colleagues report today in Nature Medicine. “You’re resetting somehow,” he says, with a clean slate of B cells that isn’t spurring autoimmune attacks.

It’s “a landmark study in the treatment of autoimmunity,” says Aimee Payne, a dermatologist and immunologist at the University of Pennsylvania who has studied a different version of CAR-T therapy for another autoimmune disease, a dangerous blistering skin condition called pemphigus vulgaris. After initial studies in mice, Payne is now involved in a clinical trial sponsored by a company she co-founded, Cabaletta Bio, that has shared results on 15 patients so far. Some patients experienced a temporary improvement in symptoms, and that therapy is gentler—the first 15 didn’t get chemotherapy before receiving their T cells (a subsequent cohort will get a reduced chemotherapy regimen), and the cells are modified to wipe out only a subset of B cells. To Payne, one of the most startling findings in Schett’s study was that the intensive therapy appeared safe for those five patients. “This did not flare disease,” she says. “That’s stunning.”

Schett now wants to try CAR-T therapy in more lupus patients, as well as some with other autoimmune conditions. Recently he treated one patient with scleroderma and another with myositis. Early next year, he plans to launch a clinical trial with 24 additional patients who have either lupus or one of these conditions. Durability of treatment will be key, because CAR-T therapy isn’t a treatment that’s designed for repeated use because of its potential risks and high cost. “If you can stay 3 years or longer in drug-free remission,” he says, “it’s a pretty great story.”