CAR T and Related Therapies Home In on Autoimmune Disease

At the 2024 Cell & Gene Meeting on the Mesa last month, former FDA Commissioner Scott Gottlieb suggested that CAR T therapies for autoimmune diseases are at an inflection point. Indeed, several companies developing CAR T cells and related therapies are setting their sights not only on their traditional domain of cancer, but on certain autoimmune conditions as well, aiming to tune the immune system not to fight disease but to stop attacking its own body.

“In the next couple of years, I do think that some of the work with CAR T in the autoimmune indications looks so transformative that that’s going to capture a lot of popular attention,” Gottlieb told attendees.

This shift is widely traced to a series of small studies led by Georg Schett of the German Center for Immunotherapy, the first of which—a case study—was published just three years ago. Schett and his colleagues have focused on patients with severe systemic lupus erythematosus (SLE) and other conditions linked to rogue B cells that attack the body itself. They treated them with autologous CAR T therapy targeting CD19, a marker found on B cells, to deplete the cells, and reported that this led to long-lasting disease remission.

“They were showing patients who had pretty severe disease going into a complete remission, and being off all drugs,” including immunosuppressives, said PJ Utz, a Stanford University researcher who studies autoimmune disease but was not involved in Schett’s studies. “To me, it’s pretty incredible.” Other academic studies and case reports have observed similar results.

While oncology and autoimmune disease are very different domains, from a scientific standpoint it’s not surprising that therapies aimed at adjusting the workings of the immune system would show promise in disorders where that system is at fault. Still, shifting in this new direction is no small task, said Kristin Yarema, CEO of Poseida Therapeutics.

“The trial designs are different. The expectations are different. The regulatory paths are different. You know, it really is quite different” from developing immunotherapies for cancer, she told BioSpace. “So I think smart companies need to understand that you don’t just need a depth of capabilities and know-how in cell therapy, and maybe your oncology experience. You really need to understand autoimmune disease at a very deep level as well.”

Despite these challenges, multiple companies are forging ahead in the space, including Poseida, Bristol Myers Squibb and Kyverna Therapeutics. Some, as in Schett’s studies, are using autologous CAR T regimens similar to those currently approved for cancer, while others are pursuing newer modalities such as allogeneic CAR Ts or T cell engagers, themselves not cell therapies but antibodies that influence T cell activity. All hope to make a mark among a diverse, stubborn and sometimes debilitating group of diseases.

In its second-quarter update this year, Arcellx, which develops CAR Ts for cancer, announced that the FDA had cleared its investigational new drug (IND) application for a CAR T product called anito-cel in the autoimmune disease myasthenia gravis. In that disease, antibodies attack proteins in the neuromuscular junction, causing muscle weakness and related symptoms. Anito-cel targets BCMA, a marker on the surface of antibody-producing B cells.

“The idea is if you can kill the cells that cause the thing that causes the disease, then you’re going upstream of the disease and eliminating the problem,” Chris Heery, chief medical officer of Arcellx, told BioSpace.

When it comes to anito-cel—which Arcellx is also developing for multiple myeloma, in partnership with Kite Pharma—Heery said that what makes the therapy unique is its use of a synthetic binder the company calls the D-domain. Compared with other chimeric antigen receptors, the D-domain is smaller and more stable, he said, and as a result, more of it tends to end up on the cell surface. That enables the company to design D-domains with lower affinity and avidity for their targets than they would otherwise need to achieve a therapeutic effect, which Heery allowed sounds counterintuitive. “But it turns out that lower affinity and lower avidity is actually more consistent with native natural biology for T cells,” he said.

For currently approved CAR T cancer therapies and in Schett’s SLE studies, patients typically receive chemotherapy that kills off a lot of circulating immune cells, or lymphocytes, and makes way for the altered, expanded cells to be infused back into the body, a process called lymphodepletion. Heery said it’s not yet clear whether that would also be the case for anito-cel and myasthenia gravis, although for multiple myeloma the treatment has so far been studied with lymphodepletion. For the autoimmune condition, “what we’ll do most likely is start with it . . . See if we get the type of deep and durable benefit that we want,” he said. “And if we do, then we may try scaling back on lymphodepletion from there.”

Like Arcellx, Poseida is hoping that a CAR T originally developed for multiple myeloma will prove to be an effective autoimmune therapy as well. Unlike Arcellx, Poseida specializes in allogeneic, or off-the-shelf therapies, meaning that cells from a single donor could be altered, expanded and given to many patients. Yarema said this could enable the democratization of CAR T therapies by avoiding the need to harvest and modify each person’s cells in a specialized center.

Rather than using a viral vector to insert a CAR into T cells, Poseida uses electroporation to open the cells up and get transposons and a gene editor inside, Yarema explained. One advantage of avoiding viral vectors is that without their space constraints, the company is able to insert multiple CARs into a single cell, she said. Another is that a virus would cause T cells to differentiate, whereas Poseida’s transformation method keeps them at a less-differentiated state called stem cell–like T memory cells. That appears to be beneficial for efficacy and safety, at least in treatment of cancer, Yarema said.

The company hasn’t yet started testing the therapy, P-BCMACD19-ALL01, in autoimmune disease, or even specified which autoimmune condition or conditions it will target. The cells carry CARs for both CD19 and BCMA, so the conditions most likely to see benefit are those that involve plasma cells and other types of B cells, Yarema said. Examples include multiple sclerosis, myasthenia gravis and systemic sclerosis.

In addition to that preclinical candidate, Poseida has two early clinical-stage allogeneic CAR Ts it is developing for cancers in partnership with Roche. One targets BCMA, while the other targets both CD19 and CD20, antigens associated with most kinds of B cells. Those programs “may also have applications to autoimmune disease,” Yarema said.

Whether autologous or allogeneic, CAR T therapies all involve programming T cells to attack cells at the root of a targeted disease. Some companies in the oncology space have been using a non–cell therapy known as T cell engagers as a means of tackling the same goal; the class is already on the market for certain cancers, including multiple blood cancers and extensive-stage small cell lung cancer. Multiple companies are working on expanding the ranks of T cell engagers on the market, for autoimmune diseases as well as for cancer.

Among them is Cullinan Therapeutics, a Cambridge, Mass.–based company formerly called Cullinan Oncology. Last month, Cullinan announced that its T cell engager CLN-978, originally developed for a form of non-Hodgkin’s lymphoma, received FDA clearance for a Phase I study in lupus. CLN-978 is the first CD19 T cell engager to receive IND clearance for autoimmune disease, according to Cullinan. Expanding its indications from oncology into autoimmune disease was a “natural progression” for Cullinan, Chief Medical Officer Jeff Jones told BioSpace.

T cell engagers are bispecific antibodies that connect to a T cell on one side, while the other side of the drug molecule binds to the target. In CLN-978’s case, the target is CD19.

While the mechanism enabling T cells to home in on a target is the same, Jones said T cell engagers potentially have several advantages over CAR Ts. One is that the manufacturing process for antibodies is simpler than for cell therapies. Another, he said, is that the drug could be injected subcutaneously rather than intravenously, making it more convenient and lessening the risk of injection-related side effects. While it’s not yet clear how many doses of CLN-978 would be needed to treat a patient, Jones said another benefit of subcutaneous administration is that it would more easily allow for multiple doses if warranted. And T cell engagers would not require lymphodepletion.

“For many diseases like SLE, many of the treatments that have been available to patients have been directed at limiting symptoms. . . . But what T cell–redirecting therapies offer is an opportunity to change the natural history of the disease and to actually provide an opportunity for remission where none had existed before,” Jones said. “And if T cell engagers can do that in a more patient-friendly fashion that can be more widely adopted in all of the various practice settings where patients receive their care, it’s really a potential to do something transformative in autoimmune diseases very broadly.”

Just how broad the application of T cell–redirecting therapies might be in autoimmune disease is still very much an open question. There are more than 100 of these conditions, according to the Cleveland Clinic, and collectively they’re very common, affecting one out of every 15 people in the U.S.

There’s also the question of which patients with a given diagnosis might be good candidates for a CAR T or T cell engager. In oncology, no CAR T has so far been approved as a first-line therapy; instead, they’re offered to patients for whom other drugs have failed. Similarly, studies such as Schett’s have so far focused on patients with relatively severe autoimmune disease who have not responded to other types of therapy.

But Yarema suggested that down the road, providers could become receptive to trying CAR Ts soon after an autoimmune diagnosis. She said that in the past, physicians’ mentality tended to be that treatment should start with drugs with mild effects and work up to stronger ones if needed, but that has shifted in multiple diseases to a paradigm of “hit it very hard, hit it early, try to drive deep remissions in the patient. Because that leads to better outcomes.” With that in mind, “I could see [cell therapies] becoming a new standard of care even relatively early in a patient’s treatment,” Yarema said.

Alongside his optimism, Utz cited several drawbacks and reasons for caution with CAR Ts. Some case studies have emerged of autoimmune patients treated with the therapy who eventually relapsed, “so it does not appear to be a cure, at least not for everybody,” he told BioSpace. Autologous cell therapies are “challenging to do,” and the need for chemotherapy is another negative, he said. Finally, it remains to be seen whether people whose B cells have been depleted by these treatments will be able to develop an antibody response when vaccinated or will remain vulnerable to infection in the short or long term.

Yet current treatments for many autoimmune diseases, such as steroids, have their own drawbacks. “Patients are really looking for . . . therapeutic options that not only really bring the disease under control or to remission but give patients freedom from having to take medication all the time, which is a constant reminder of the disease,” Yarema said. Cell therapy “is going to be the kind of therapy that the patients have been waiting for for a very long time.”

Correction (Nov. 4): This article originally identified Jeff Jones as Cullinan Therapeutics’ CEO; in fact, he is the company’s chief medical officer. BioSpace regrets the error.