On the cusp of a CAR T cell cure for lupus

The first sign that something wasn’t right started with her hands. As a seemingly healthy 19-year-old college student, Dina Thachet noticed painful swelling in her fingers that seemed to have come out of nowhere.

“It was February in Chicago, so the doctors at the student center chalked it up to, ‘It's cold. Put on an extra pair of gloves,’” she said.

The seemingly random symptoms didn’t stop. Her hair started falling out, and she had malaise. “Within two days, I lost 13 pounds. I started wasting away,” Thachet said. “I was told I was a hypochondriac. I was told I was crazy, that I was making it up, looking for attention.”

Her parents believed her, though, and took her to more doctors and specialists, but physicians didn’t begin to take her seriously until Thachet ended up in the emergency room with meningitis and an intestinal infection that had spread to her blood. After a three-hour consultation with a rheumatologist, she finally got some answers.

This is lupus. We’ve never seen 100 percent response rates from anything. Do we know that all the different versions of CAR T that are being proposed are going to result in that same drug-free remission? I don’t know, so I think that the unknown is part of what’s giving everybody pause.
- Anca Askanase, Columbia University and the Lupus Foundation of America

“I was diagnosed with systemic lupus erythematosus, and then subsequently, a kidney biopsy showed that I had stage four lupus nephritis,” said Thachet. “My kidneys were functioning at about seven to nine percent, in that range, and I subsequently started on chemotherapy right away. It was lifesaving.”

Thachet is now a lupus advocate and board member at the Lupus and Allied Diseases Association (LADA). While she takes multiple medications to keep her condition under control, she never truly gets a break from it. “It impacts every single aspect of our lives,” she said.

Lupus is a chronic autoimmune disease that affects multiple regions of the body from the joints to whole organ systems such as the heart, kidney, and brain. It is a heterogeneous condition with people presenting with diverse symptoms in a range of severities. Ninety percent of those diagnosed with lupus are young women like Thachet (1).

In lupus, B cells are the major players in disease pathogenesis. They produce antibodies that target a person’s own proteins and serve as antigen-presenting cells where they bind self-proteins and present them to T cells as foreign (2). These pathogenic B cells also release both pro- and anti-inflammatory cytokines (3). All of these activities cause a person’s immune system to attack their own organs and tissues, leading to severe organ damage without treatment.

Until recently, most lupus treatments acted by dampening the immune system in a nonspecific way using approaches such as nonsteroidal anti-inflammatory drugs, corticosteroids, or the antimalarial drug hydroxychloroquine. In 2011, however, the FDA approved the first drug specifically developed for lupus, a monoclonal antibody called belimumab (brand name: Benlysta) that targets the cytokine B lymphocyte stimulator (BLyS) (4). BLyS promotes the survival of B cells that produce autoantibodies. Just ten years after that, the biologic anifrolumab-fnia (brand name: Saphnelo) was approved for adults with lupus. Anifrolumab-fnia inhibits type I interferon signaling, which is elevated in people lupus (5).

While both anifrolumab-fnia and belimumab have improved lupus care over the past decade, neither is a cure. They don’t work for all patients, and for those they do, administration is required every few weeks.

Now, recent data from a small number of patients showed that a one-time infusion of chimeric antigen receptor (CAR) T cells may put lupus in long-term remission. Lupus researchers and advocates eagerly await results from multiple early-stage clinical trials from different biopharmaceutical companies testing whether this cell therapy that has worked well for treating cancer may also treat or potentially cure lupus once and for all.

The first patients

CAR T cell therapies have proven incredibly effective for treating blood cancers, including those that affect B cells such as large B cell lymphoma. Cancer cells are simply a person’s own cells that have turned against them — just like in an autoimmune disease such as lupus — so it follows that the same CAR T cell strategy might be effective for this disease.

“By ensuring a proper depletion of the pathogenic B cells that are driving the disease, it could help control this autoimmunity,” said Dominic Borie, the President of Research and Development at Kyverna Therapeutics. “A way to achieve that would be through this cell therapy approach where cells can navigate freely in the body and go find B cells that are not only in the peripheral blood where monoclonal antibodies can go, but in particular, in tissues where B cells reside.”

Monoclonal antibodies such as the recent FDA-approved lupus treatments can’t easily traffic into tissues, which means that they can’t target the B cells there. Cancer studies have shown that CAR T cells have no problem infiltrating tissues such as lymph nodes to find and kill cancerous cells there.

Dominic Borie wears a pink shirt and stands in a laboratory.

Dominic Borie and his team at Kyverna Therapeutics are developing a CAR T cell therapy for lupus.

Credit: Kyverna Therapeutics

Preclinical data from lupus mouse models indicated that CAR T cells are very effective at targeting and depleting pathogenic B cells (6). The lupus mice that received CAR T cells targeting CD19, a receptor on the surface of B cells, had all of their B cells depleted, lived longer than untreated mice, and had their lupus go into remission.

The first hint that CAR T cells might also be a way to treat people with lupus appeared in a 2021 Correspondence to the New England Journal of Medicine (7). There, a group of researchers at Friedrich-Alexander-University Erlangen–Nuremberg led by scientist Georg Schett described a 20-year-old woman with severe lupus who had tried almost every possible treatment. The researchers gave her a single infusion of CD19 CAR T cells. They found that she had no adverse reactions to the treatment, and her circulating B cell level decreased rapidly along with her level of autoantibodies. The patient looked like she was in complete remission.

Fast forward to 2022, Schett and his team expanded their study to five patients. They reported in Nature Medicine that four women and one man treated with CD19 CAR T cells went into complete remission three months after treatment (8). All five of the patients remained in remission at the time of the study follow up period one year later. About three to four months after the treatment, healthy B cells appeared in the patients, indicating that the CAR T cells removed the pathogenic B cells and also reset the patients’ immune systems, allowing them to have normal functioning B cells.

“Those five cases that were initially described by Georg Schett and the Erlangen group, they made everybody beyond energized and just excited,” said Anca Askanase, a lupus researcher at Columbia University and a member of the Medical-Scientific Advisory Council at the Lupus Foundation of America. “We do need to provide a word of caution and be mindful that the data so far are limited, and the information that we have is just a little too cursory for us to be promising the cure.”

More clinical research is needed, and multiple biopharmaceutical companies have stepped up to the plate.

Calling all CAR T cells to the clinic

For the researchers at the cell therapy company ImmPACT Bio, now part of Lyell, the lupus data from the Schett team inspired them to see if the bispecific CD19/CD20 targeted CAR T cell therapy that they had developed for B cell non-Hodgkin lymphoma could work for lupus.

“[The] Nature Medicine article really got us fired up to launch our own autoimmune program,” said Jonathan Benjamin, Chief Medical Officer of ImmPACT Bio.

By targeting both CD19 and CD20 B cell receptors, the researchers at ImmPACT Bio engineer their CAR T cells to have a better chance of finding and killing all of the pathogenic B cells present in someone with lupus.

ImmPACT Bio researchers and lupus advocates stand in a row indoors at ImmPACT Bio’s offices.

Lupus advocates, Kathleen Arntsen (second from left) and Dina Thachet (center) talked about their lived experience with lupus with the researchers at ImmPACT Bio. Left to right: Sylvain Roy, Chief Technical Officer of ImmPACT Bio; Arntsen; Thachet, Jim Johnson, former Chief Scientific Officer of ImmPACT Bio; and Jolie Keough, Vice President of Human Resources at ImmPACT Bio.

Credit: Kathleen Arntsen

“Part of the reason for that is that there is variability in the cell surface protein expression, even in B cells. Whereas CD20 is typically restricted to CD19 positive B cells, there can be variable expression of CD19,” Benjamin explained. “There’s published literature and we’ve observed it in samples that we’ve obtained, that CD19 is expressed at lower levels on B cells from patients with lupus.”

The researchers at Kyverna Therapeutics also have their own CAR T cell therapy for lupus, which was originally designed by researchers at the National Institutes of Health (NIH). While their CAR T cells only target the CD19 receptor on B cells, they aim to make their therapy safer than the currently approved ones by designing the piece that binds CD19 fully human. This component on the approved CAR T cell therapies is of mouse origin, which increases the risk of an adverse immune response.

“Immunogenicity is very important for autoimmune disease. Patients will tend to mount immune responses to foreign proteins or even their own proteins, but even more so, against foreign proteins, so we thought it would be important for autoimmune disease patients to have a fully human construct,” said Borie.

The researchers at the NIH also designed this CAR T cell construct to produce fewer cytokines than the currently approved therapies, lessening the risk of cytokine release syndrome (CRS), which is a dangerous side effect of CAR T cell therapy.

The researchers at ImmPACT Bio also wanted to minimize the risks of CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), which can occur after CAR T cell therapy. To do that, they designed their CAR to include a costimulatory domain that leads to a slow expansion of CAR T cells in the body, decreasing the risk of neurotoxic side effects (9). This costimulatory domain also leads to lower amounts of cytokine release in the early stages of CAR T cell treatment, which is associated with a decreased risk of CRS.

Patients who have lupus, who don’t necessarily have a malignancy but have a very serious condition nonetheless, may not be as familiar or comfortable with the side effect profile that typical oncology therapeutics may offer.
– Jonathan Benjamin, ImmPACT Bio

While the risk of CRS or ICANS may be acceptable to patients receiving CAR T cells as cancer treatments, autoimmune diseases, though chronic, are not the same as cancers. “Patients who have lupus, who don’t necessarily have a malignancy but have a very serious condition nonetheless, may not be as familiar or comfortable with the side effect profile that typical oncology therapeutics may offer,” said Benjamin.

Reducing these risks is front of mind for the many biopharmaceutical companies testing CAR T cell therapies in early clinical trials right now. These include the ImmPACT Bio team, who are recruiting patients with lupus for a Phase 1/2 trial in the United States and an exploratory trial in China. The Kyverna Therapeutics team already has a Phase 1/2 trial underway in Europe, and they are recruiting for a Phase 1 trial in the United States now as well. Researchers at Miltenyi Biomedicine, Cabaletta Bio, Bristol-Myers Squibb, Novartis, and others also have clinical trials of CAR T cell therapies for lupus in early stages.

Researchers from Novartis presented preliminary results from their Phase 1/2 CAR T cell therapy trial for lupus at the American College of Rheumatology Convergence conference in November 2023 (11). Of the three patients included in the results, two experienced mild or moderate CRS, but all of them had B cell depletion as well as decreases in lupus disease severity. More recently, the Cabaletta Bio team reported that one patient with lupus in their CAR T cell trial experienced severe ICANS, but it resolved quickly with treatment.

Schett’s team also published additional data on CAR T cell therapy for eight people with lupus as well as three with idiopathic inflammatory myositis, and four with systemic sclerosis (12). Again, all of the lupus patients entered remission following the treatment.

“I’m excited to live in this time of redefining and reshaping treatments for lupus,” said Askanase. “We need to do the work to fully understand where these drugs fit, the full extent of their efficacy and safety, and how to use [them] to [lead to] better outcomes in lupus and ultimately the lives of people living with lupus.”

A lupus-free future?

As CAR T cell therapies for lupus work their way through clinical trials, the main questions that remain are how well each of these different CAR T cell therapies will work for different people with lupus and how long lupus remission will last.

Anca Askanase wears a stethoscope while touching a woman’s hand in a doctor’s office.

Lupus researcher Anca Askanase is excited about the prospect of CAR T cell therapy for lupus.

Credit: Anca Askanase, Columbia University

“This is lupus. We’ve never seen 100 percent response rates from anything,” said Askanase. “Do we know that all the different versions of CAR T that are being proposed are going to result in that same drug-free remission? I don’t know, so I think that the unknown is part of what’s giving everybody pause.”

Borie agreed and added that Kyverna Therapeutics is developing a biomarker program to identify people with lupus who will be most likely to benefit from the treatment. As companies report more of their clinical trial data, a better understanding of how exactly CAR T cell therapy treats lupus will emerge.

Whether CAR T cells present an actual cure for lupus remains to be seen. “We hesitate to use the ‘c-word,’ but I think it’s a long-lasting treatment-free and disease-free condition. If that’s verified through many patients enrolled in large clinical trials, then maybe we’ll be able to say, ‘Okay, well, maybe they’re getting close to the cure,’ but it’s a little bit too early to have this high expectation,” said Borie.

In the meantime, people with lupus are keeping a close eye on these clinical trials. Kathleen Arntsen, a person with lupus as well as the President and Chief Executive Officer of LADA, explained that right now she takes more than 40 medications daily. The prospect that a single infusion of CAR T cells could potentially put her lupus and that of others in remission is exhilarating.

“It’s revolutionary, and it’s just given us such tremendous inspiration and motivation,” she said. “We are sitting here earnestly, eagerly waiting for these new therapies to make it all the way through to patients.”