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Destroying B cells, like the one shown here, helped mice with lupus revert to good health. 3D4MEDICAL/SCIENCE SOURCE

Genetically engineered immune cells wipe out lupus in mice

By Jennifer Couzin-FrankelMar. 6, 2019 , 2:00 PM

Lupus can be a stubborn disease to treat. Although many struck by the autoimmune condition live relatively normal lives, some suffer from kidney failure, blood clots, and other complications that can be deadly. Now, scientists have found that a novel treatment that wipes out the immune system’s B cells cures mice of the condition. Though the work is preliminary, it has excited researchers because it uses a therapy already approved for people with blood cancer.

“This is a critical stepping stone,” says Jennifer Anolik, a rheumatologist who runs the lupus clinic at the University of Rochester Medical Center in New York who was not involved with the work.

The strategy is known as chimeric antigen receptor (CAR)-T therapy. It involves genetically engineering T cells, the sentries of the immune system, so they recognize and destroy certain cells in the body. Although it comes with potentially serious side effects, it can be lifesaving. The approach took the cancer world by storm in 2011, after scientists reported saving patients with an advanced form of leukemia. Since then, it has been approved to treat certain leukemias in children and lymphomas in adults. Although CAR-T therapy can target different cells, the approved treatments hunt down and destroy B cells by spotting a protein marker, CD19, that almost all B cells sport on their surface.

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Since CAR-T therapy emerged, scientists who study autoimmune diseases have eyed it with interest because B cells are involved in many of these diseases. B cells can release autoantibodies that damage the body’s tissue and provoke T cells into attacks on tissues as well. In 2016, a team at the University of Pennsylvania reported that mice with a rare autoimmune disease called pemphigus vulgaris were helped by CAR-T therapy.

But lupus has presented a puzzle. An antibody called rituximab, which depletes B cells and is often prescribed to patients with rheumatoid arthritis and multiple sclerosis, failed to help many people with lupus in two large clinical trials. That “caused a bit of head-scratching,” says Marko Radic, an immunologist at the University of Tennessee Health Science Center in Memphis.

Did the results mean B cells weren’t important in lupus after all? The answer is no, suggests Mark Shlomchik, an immunologist at the University of Pittsburgh in Pennsylvania who was not involved in the new study. He believes rituximab stumbled in part because of an unfortunate confluence of how the antibody works and how the immune system falters in lupus. Rituximab needs immune cells called macrophages to step in and assist in B cell destruction. That works in some diseases, but in lupus, those cells can be “paralyzed,” says Shlomchik, and struggle to pull this off.

Enter CAR-T therapy, where T cells become efficient B cell slayers without needing a helping hand. Radic and his colleagues tested the approach in two mouse models of lupus. After the mice got sick, the team exposed them to whole-body radiation to wipe out existing immune cells. (People getting CAR-T therapy receive chemotherapy for the same purpose.) Then, the scientists infused the genetically altered T cells into 41 animals.

In 26 of the mice, the CAR-T cells successfully destroyed the B cells with CD19—nearly all of them—and those cells never reappeared. That’s similar to what’s been observed in cancer patients who undergo CAR-T therapy. The effects on mouse health surprised even Radic, who’d had high hopes: The animals’ spleens, skin, kidneys, and other body parts showed no remaining signs of lupus, the team reports today in Science Translational Medicine. “We were so impressed,” Radic says.

Most of the animals that were successfully treated lived for more than a year after treatment, a long stretch in mouse-time. Animals that got placebo therapy all died within 8 to 10 months, and many perished earlier.

Anolik says she would like to better understand why CAR-T therapy didn’t work for 15 mice. But she’s hopeful for the treatment’s future for her patients and others.

The findings are “very compelling,” Shlomchik says. In some patients, lupus is “as aggressive as cancer,” he says, so even a drastic treatment could make sense.Posted in: 

doi:10.1126/science.aax2489

Jennifer Couzin-Frankel

Jennifer Couzin-Frankel

Staff Writer

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