CAR T-Cell Therapy Helps Lupus Patients Enter Remission In Small Study

An immunotherapy used to treat blood cancer also shows promise as a treatment for lupus, new research shows.

The news comes from a small study, published last week in Nature Medicine, in which German researchers treated five patients with systemic lupus erythematosus (SLE) with autologous chimeric antigen receptor (CAR) T-cell therapy.

The treatment, given in a single dose, induced remission in all five patients within three months—and they remained in remission for an average of eight months after treatment, according to the study authors. The first person to receive CAR-T treatment as part of the study was still in remission more than a year later.

Though the study was small, the findings are still "very important" for the autoimmune disease community.

"The reason why it is important to the field is that it really opens up opportunities in the future for using adoptive cell therapies for patients with lupus," Maximillian Konig, MD, an instructor of medicine in the Division of Rheumatology at the Johns Hopkins University School of Medicine, who was not involved in the research, told Health.

A Personalized Approach to Treatment

The Food and Drug Administration (FDA) approved the first CAR-T therapy in 2017, to treat lymphoma in people whose cancer relapsed.

The treatment, a type of immunotherapy called personalized cell therapy, harnesses a person's own immune cells to kill cancer cells. It works by using modified versions of a person's T cells, a type of white blood cell, to recognize and attack proteins on the surface of problematic cells. In cancer patients, the target is malignant B cells that have multiplied out of control.

Before the treatment can start, a person's unique T cells are extracted and sent to a lab to be tweaked to allow them to identify and attack B cells, which include the cancerous B cells that make up the person's tumors. A few weeks later, the patient receives an infusion of their modified cells, which get straight to work killing the target cells.

The reason it works so well in blood cancers is because unlike solid cancers—such as breast, lung, and kidney cancers—the proteins on the surface of blood cancer cells are homogeneous, or uniform, giving a single target for the CAR T-cells to latch onto.

Autoimmune disease experts have long had a hunch the immunotherapy could be useful in attacking the overactive B cells that underlie lupus and other autoimmune diseases.

"In lupus, you don't have malignant B cells, but you do have autoimmune B cells that attack your cells and cause inflammation," lead study author Georg Schett, MD, vice president of research at Friedrich-Alexander-Universität Erlangen-Nürnberg, in Erlangen, Germany, told Health.

Essentially, these B cells mistake a person's own cells for intruders and attack, causing a cascading inflammatory response that affects the skin, joints, organs, nervous system, blood cells, kidneys, or some combination of these.

SLE, or systemic lupus, accounts for 70% of all lupus cases and most people do respond to existing therapies. "But some don't, so we need to find a better solution for them," said Dr. Schett.

'Rebooting' the Immune System

The new study was built off of research Dr. Schett and his team published last year. The single case study showed that CAR-T therapy induced remission in one woman who had unmanaged lupus.

For the new study, the team recruited five adults with severe lupus whose disease was not under control using existing drugs. The median age was 22 and the disease had been active for between four and eight years.

The participants' T cells were genetically modified to find and attack a protein called CD19, which sits on the surface of the B cells implicated in lupus flare-ups. Before the cells could be infused back into their bloodstream, everyone had to receive two conditioning drugs that essentially delete most of the immune system, which allows the CAR T-cells to integrate back into the body.

The drugs—fludarabine and cyclophosphamide—are used by themselves to induce remission in people with lupus. Although the drugs likely play some role, "The CAR T-cells do still appear to be doing the heavy lifting because when the other drugs are gone, remission stays," said Dr. Konig.

Once the CD19-programmed CAR T-cells were infused back into the patients' bodies, they essentially erased all of the B cells that contain the CD19 protein. Over time, their stem cells in the bone marrow produce new B cells to replace the old ones, this time without the ability to restart autoimmunity.

"What happens is you do a reboot of the B cell system with naive immune cells and without the autoimmune cells," said Dr. Schett, adding that unlike current lupus treatments that attack B cells, CAR-T is a one-time injection, rather than a prolonged therapy.

The current treatments also can't penetrate as deeply into the body's tissues as CAR-T does, meaning they leave some of the targeted cells behind to continue to cause a flare. The patients that received CAR-T are still being followed an average of 8 months following their treatment and all five remain in remission.

"The biggest surprise was that the disease did not reoccur when the B cells repopulated," said Dr. Schett. "You would have thought that when the B cells reoccurred, the disease would have reoccurred, but we have patients whose B cells reoccurred a year ago and they still are not sick."

A Promising Treatment—For Some

According to Dr. Konig, even if future research demonstrates that CAR-T therapy is a safe and effective treatment for lupus, it will likely be available only to people whose disease cannot be managed with other therapies.

The treatment isn't without risk, and the benefits have to match those risks for each individual patient, he said. Currently, CAR-T cells are not selective, meaning the engineered fighting machines wage war against all B cells with the CD19 surface protein— including those that protect the body from infection.

There's also the fact that not all B cells are the same, and not all of the cells that may cause inflammation have the CD19 surface protein that was targeted in the study. Other B cells, called long-lived plasma B cells, have also been implicated in lupus inflammation and do not have CD19, meaning those B cells would not have been destroyed by CAR-T.

"In some patients, long-lived plasma B cells may play a bigger role in their lupus and this might not work for them," said Dr. Konig.

Still, the results are a huge step forward in exploring CAR-T for lupus.

"It is very insightful to see that just depleting the CD19 B cells seems to be enough to get lupus under control," said Dr. Konig. "This should give us huge hope for patients with lupus and it tells us something important mechanistically that has not been understood about the disease until now."

Though none of the participants in the new study had issues with infection after their B cells were depleted, that is a concern. According to Dr. Konig, many people treated with CAR-T for leukemia and lymphoma suffer from infections when their B cells are depleted for a period of time.

"Whether this applies to patients with lupus is still unknown," he said. "It's very encouraging that over the course of this study, there weren't any major infections."

All six of the lupus patients treated with CAR-T in Germany—the current study and the previous case study— accessed the therapy through the Compassionate Use law, which allows patients to access experimental, unproven treatments when nothing else has worked.

Before the therapy becomes available to patients, clinical trials will need to test not only CAR-T, but compare a CAR-T group to a group of patients treated with just the conditioning drugs to determine how much of an effect these therapies have on their own, said Dr. Konig.

"These therapies will not quickly become standard of care for all lupus patients," said Dr. Konig. "For now, this is a promise of a future."