Virus World

Engineered immune cells have given 15 people with once-debilitating autoimmune disorders a new lease on life, free from fresh symptoms or treatments. The results raise hopes that the approach — called CAR-T-cell therapy — might one day be extended to a variety of other conditions fuelled by rogue immune cells that produce antibodies against the body’s own tissues. All 15 participants, who each had one of three autoimmune conditions, have remained disease-free or nearly so since their treatment, according to data presented on 9 December at the American Society of Hematology meeting in San Diego, California. The first participants were treated more than two years ago. These successes, although preliminary, have been electric, says Marco Ruella, an oncologist at the University of Pennsylvania in Philadelphia. “We’re all excited,” he says. “There’s a lot of potential.”

Bespoke immune cells

CAR-T therapies harness the immune players called T cells. T cells are removed from the person being treated, genetically engineered to produce proteins called chimeric antigen receptors (CARs) and then reintroduced to the person’s body. In many therapies, the T cells are tailored to recognize a protein made by immune cells called B cells. When reintroduced, the CAR T cells will target the B cells for destruction — a useful feature for treating cancers caused by abnormal B cells. B cells also drive some autoimmune disorders by making antibodies that attack healthy tissue. In 2019, researchers showed that CAR T cells that recognize B cells reduced symptoms in mice with a disease similar to lupus, an autoimmune disorder that affects a variety of organs1. Around the same time, researchers at University Hospital Erlangen in Germany were setting up their own CAR-T centre to provide cancer treatment. During a meeting at the centre, a rheumatologist asked the cancer specialists for advice about a young woman with a form of lupus called systemic lupus erythematosus. Several of her organs were failing; her doctors estimated that she did not have long to live. The young woman insisted that they try something new.

High-risk approach

The team thought of the mouse study but baulked at trying it in people. CAR-T therapy can have severe side effects, and recipients must first undergo intensive chemotherapy that kills off many of their existing immune cells. “At the beginning we were quite scared,” said team member Fabian Müller, an oncologist at the Friedrich–Alexander University of Erlangen–Nuremberg, at a press conference before he presented the work at the San Diego meeting. The woman was adamant that they try. That first participant — and the others who followed — experienced relatively minor adverse effects, Müller reported at the conference. The Erlangen team eventually used the method to treat two other autoimmune disorders: systemic sclerosis and idiopathic inflammatory myositis. The successes continued. Other groups have since taken up the approach and reported similar results. Earlier this month, another team added a fourth autoimmune disorder called myasthenia gravis to the list of successes2. Researchers are beginning to wonder how long the final list will be. “We’re just at the beginning,” says Marcela Maus, who designs CAR-T therapies against cancer at Massachusetts General Hospital in Boston. “There is so much that can be done that was unthinkable just a decade ago.” At this stage, however, it’s unclear how much of this success is due to the CAR-T therapy as opposed to the chemotherapy that killed many of the participants’ pre-existing immune cells, cautions Ruella. That might have helped to wipe out the errant B cells. For now, Müller lapses into a dreamy smile as he marvels over the remarkable recoveries he has seen: the man who struggled to walk 10 metres before his treatment and now routinely walks 10 kilometres around town, for example. “These are young people that have been spending more time with their doctors than with their friends,” he says. “They would describe their breakfast as a handful of pills that they are just shoving in.”

December 12, 2023

https://doi.org/10.1038/d41586-023-03968-6

A mouse study with engineered “CAR T cells” shows a novel way to stop the virus. Drugs work stunningly well to control HIV—but not in everyone, and not without side effects. That's why a small cadre of patients known as elite controllers has long fascinated researchers: Their immune system alone naturally suppresses HIV for decades without drugs. Now one team, inspired by success in mice, hopes to endow HIV-infected people with tailormade immune cells that target HIV, in effect creating elite controllers in the clinic.

The immune strategy has risks, but it builds on increasingly popular cancer treatments with T cells engineered to have surface proteins, called chimeric antigen receptors (CARs), that can recognize markers on the surfaces of tumor cells and destroy the cancer. Such CAR T cells can also be tailored to identify and eliminate HIV-infected cells. This approach was tested in HIV-infected humans long before CAR T cells proved their worth against cancer, but it roundly failed. The field wants "to move what's been learned from cancer back to HIV, completing the circle," says Steven Deeks, an HIV/AIDS clinician at the University of California, San Francisco, who first tested a CAR T cell against the virus in the late 1990s. The new study—conducted by researchers from the University of Pittsburgh in Pennsylvania; the biotech company Lentigen in Gaithersburg, Maryland; and the Albert Einstein College of Medicine in New York City—uses a far more sophisticated CAR approach than the one Deeks tested. "It's promising and seems to be more potent than what's been tried in the past," says stem cell biologist Hans-Peter Kiem, who has tested CAR T cells in leukemia and lymphoma patients at the Fred Hutchinson Cancer Research Center in Seattle, Washington.

For the new work, published online this week in Science Translational Medicine, the researchers engineered T cells to include genes encoding two kinds of CARs, each targeting a different part of HIV's surface protein. In test tube studies, this "duoCAR T" cell powerfully killed white blood cells infected with a diverse array of HIV variants, the group reports. The team also gave near simultaneous injections of CAR T cells and HIV-infected human cells to the spleens of mice with a "humanized" immune system. (Rodents cannot normally be infected with the AIDS virus.) When the group harvested spleens from the mice a week later, five of six mice had no detectable HIV DNA and their average viral levels had dropped 97.5%.

Published on August 7 2019 in Science Translational Medicine:

https://doi.org/10.1126/scitranslmed.aav5685