An emerging field with great potential

When German scientists posted data in 2022 showing that CAR-T cell therapy could be effective in treating systemic lupus erythematosus, interest in the field quickly took off. More recently, spurring interest even further, the researchers posted an update in February 2024, showing results from a case series in which 15 autoimmune disease patients, eight of which had systemic lupus erythematosus, all achieved complete remission after receiving a single infusion of CAR-T therapy.

Lupus, which affects around five million people worldwide, occurs when the immune system attacks its own tissues. The disease can range from mild to severe, and causes inflammation; in severe cases, it can also cause permanent tissue damage, which can be widespread, affecting the skin, joints, heart, lungs, kidneys, circulating blood cells, and brain. Systemic lupus erythematosus is the most common and most serious form of the autoimmune disorder. 

Lupus patients often have to take drugs their whole lives, ranging from ibuprofen to steroid tablets and injections, or other immunosuppressant or biological medicines. 

A major milestone was achieved in 2011 when GSK and Human Genome Science’s belimumab was approved by the U.S. Food and Drug Administration (FDA) as the first-ever targeted biological for the treatment of systemic lupus erythematosus patients. The drug works by suppressing the B lymphocyte stimulator protein (BLyS) – people with systemic lupus erythematosus tend to have elevated levels – making symptoms more manageable. 

However, there is still no cure for the disease, and this is exactly why there is so much excitement surrounding the potential of CAR-T therapy for lupus – it could lead to complete remission for patients. Plus, we already know from its treatment of hematological cancers just how effective this type of therapy can be. 

How can CAR-T therapy treat lupus?

We know that in oncology CAR-T therapy works by essentially finding and killing cancer cells. But how exactly does it work to treat lupus? 

Well, in this situation, it is all about B cells, a type of white blood cell that makes infection-fighting proteins called antibodies. CAR-T researchers are currently very focused on a group of autoimmune diseases referred to as B-cell-mediated diseases, which includes lupus. In this disease group, B cells in the immune system essentially go haywire and start attacking healthy cells.  

But these B cells contain a specific protein on their surface that CAR-T can recognize and target. By depleting B cells, CAR-T treatment can ultimately lead to long-term drug-free remission in patients with autoimmune diseases, as they have the potential to ‘reset’ the immune system by clearing autoreactive B-cells and selectively permitting normal naïve B-cell reconstitution. 

Many of the current approaches to CAR-T cell therapy for lupus and other autoimmune diseases involve the specific targeting of surface antigen CD19, which a B cell expresses from the beginning of its life and past middle age. This is based on the fact that, over the past couple of years, academic groups have published multiple findings demonstrating the potential of anti-CD19 CAR-T therapies to transform the course of autoimmune diseases. They appear to have higher efficacy than targeting CD20, another B-cell surface antigen, for example. 

It is worth noting that, although the B-cell targets employed in CAR-T therapies for autoimmune diseases happen to be the same as those employed in CAR-T therapies for blood cancers, side effects appear to be less severe in autoimmune patients, potentially because these patients have fewer bad B cells to eliminate than cancer patients, so the CAR-T therapy is less taxing for them. 

“We think [the absence of severe side effects] is because the target engagement with cancer is much higher—with a higher burden of B cells in the body—than in autoimmunity, so the level of CAR-T cell engagement at once is much lower,” Georg Schett, one of the researchers for the German study, explained to Fierce Biotech. “Therefore, we have less cytokine release.”  

In the clinic: CAR-T cell therapies for lupus are showing success

As mentioned, the idea of developing CAR-T therapies for lupus has really taken off in recent years among both big pharma companies and small biotechs, as each eyes up the opportunity of being the first to bring this type of therapy to the market, potentially offering a cure for the disease. 

So far, though, candidates are still working their way through the clinic trials, and a few of them certainly show enormous promise. Here are some examples of biotech companies developing CAR-T cell therapies for lupus that have recently accomplished successful milestones with their candidates. 

Cartesian Therapeutics’ CAR-T cell therapy for lupus enters phase 2 trial

Cartesian Therapeutics is very much pushing ahead with its CAR-T candidate for lupus, as the company announced in July 2024 that the first patient had been dosed in a phase 2 open-label clinical trial evaluating the therapy in patients with systemic lupus erythematosus.

The candidate, called Descartes-08, is an autologous mRNA CAR-T cell therapy that targets B-cell maturation antigen (BCMA), a surface antigen expressed by long-lived plasma cells that is correlated with systemic lupus erythematosus severity and activity, which is what makes it a promising therapeutic target.

Furthermore, in contrast to conventional DNA-based CAR-T cell therapies, mRNA CAR-T administration is designed not to require preconditioning chemotherapy and is not expected to carry the risk of genomic integration associated with cancerous transformation. Carsten Brunn, president and chief executive officer of Cartesian commented in a press release that “Descartes-08 is purposefully designed to overcome the limitations associated with the application of conventional, costly DNA-engineered CAR-T cell therapies for autoimmune diseases.”

The phase 2 study of Cartesian’s candidate will examine its safety and tolerability as an outpatient option without preconditioning chemotherapy for people with moderate or severe systemic lupus erythematosus refractory to immunosuppressants for whom existing therapies fall short. 

The company is actually primarily developing the CAR-T candidate for myasthenia gravis, another autoimmune disease, for which it recently produced durable responses in several patients treated in a phase 2b portion trial. 

Kyverna Therapeutics highlights potential of anti-CD19 CAR-T cell therapy for lupus nephritis 

Kyverna Therapeutics’ anti-CD19 CAR-T cell therapy KYV-101 is in development for lupus nephritis, a severe kidney manifestation of systemic lupus erythematosus that affects up to 50% of lupus patients and is a major cause of morbidity and mortality. 

The CAR in KYV-101 was originally designed by the National Institutes of Health (NIH) to improve tolerability and was tested in a 20-patient phase 1 trial in oncology. However, Kyverna is now evaluating it in phase 1/2 and phase 2 trials in the U.S. and Germany across rheumatologic and neuroinflammatory autoimmune disorders. As well as lupus nephritis, the specific indications it is being evaluated for are systemic sclerosis, myasthenia gravis, and multiple sclerosis. 

In November 2024, Kyverna Therapeutics announced that it would be presenting updated clinical data from lupus nephritis patients treated with KYV-101 in the ongoing KYSA-1 and KYSA-3 phase 1/2 studies. In the press release, it said that all patients at six months of follow-up after treatment at the target dose continued to display sustained efficacy and durability across numerous key clinical measures. Furthermore, KYV-101 continued to demonstrate robust safety and tolerability with no high-grade cytokine release syndrome (CRS) or immune effector cell associated-neurotoxicity syndrome (ICANS) observed.

It is worth noting, however, that one of the lupus nephritis patients in the phase 1/2 trial of KYV-101 relapsed after five months despite initially responding. Although the relapse was only the second one reported for an autoimmune CAR-T therapy, Fierce Biotech said in a recent article that Uy Ear, vice president of Mizuho, wrote in a note in June that the results might bode well for a redosable CAR-T therapy like the one currently in development by Cartesian. This is due to the fact that it doesn’t integrate into the genome of T cells and patients can be treated with it more than once without the safety risks presented by redosing DNA-based CAR-T therapies. 

“We believe these emerging [autoimmune CAR-T] data point to the need for redosing and a safer cell therapy option,” wrote Ear. “Descartes-08 confers distinct advantages – particularly on safety and for redosing, which we believe all CAR-Ts will require.”

Still, given the overall positive efficacy and safety results shown by KYV-101 so far, Kyverna will continue to push on with the candidate. 

Another anti-CD19 CAR-T therapy: Cabaletta Bio’s CABA-201 shows positive results 

Cabaletta Bio is currently running a phase 1/2 open-label study of its autologous CD19-specific CAR-T cells, called CABA-201, in active systemic lupus erythematosus and lupus nephritis. 

Following a one-time infusion, CABA-201 is designed to transiently and completely deplete all CD19-positive cells and may enable a reset of the immune system with the potential for durable remission without chronic immunosuppressive therapies in patients with autoimmune diseases. 

The company is also testing CABA-201 in phase 1/2 clinical trials in myositis, systemic sclerosis, and generalized myasthenia gravis, with potential application in a broad range of other autoimmune diseases. 

In November 2024, Cabaletta Bio announced new and updated clinical data on CABA-201 demonstrating the potential to achieve drug-free, compelling clinical responses based on eight patients dosed across ongoing phase 1/2 clinical trials, including in the trial for lupus. Consistent and complete B cell depletion was observed in all patients within the first month after CABA-201 infusion and evidence of transitional naïve B cell repopulation was observed as early as eight weeks in the first two patients.

CAR-T therapy’s pivot from cancer to autoimmune diseases 

As touched on previously, the data presented by German scientists opened up the floodgates, not just in terms of companies pivoting towards testing CAR-T therapies for lupus, but for other autoimmune diseases too. Indeed, the updated case series released in February also showed the successful use of CAR-T therapy in three idiopathic inflammatory myositis patients and four systemic sclerosis patients.

While preclinical studies hinted at CAR-T’s potential in autoimmune disease, it was academic patient studies that came out of Germany that “ignited the excitement,” Sami Corwin, a healthcare analyst at William Blair, told Fierce Biotech. “[They] kind of showed that for the first time, you might be able to induce an immune reset in severe autoimmune patients that could lead to a durable drug-free remission.” 

As of December 2023, more than 30 companies had announced plans to pursue the development of CAR-T cell therapies for autoimmune disorders, and more than 70 programs were in development, according to William Blair. 

Despite the positive results so far from clinical trials, these early studies have been small and focused on only a few autoimmune conditions. Schett told Fierce Biotech that the approach’s future effectiveness will likely hinge on disease and patient selection; the disease should be truly B-cell mediated, and patients can’t have so much organ damage that it precludes improvement. He also said that results could vary according to target selection, lymphodepletion, and whether the patient is on other kinds of drugs that might affect T cells.   

Given that this is still an emerging field and is not yet quite as advanced as using CAR-T therapy for cancer, we will just have to wait and see what happens. 

But the recent trials testing CAR-T therapies in lupus certainly appear to have shown very positive results so far and could potentially offer autoimmune disease patients a chance at remission.