Race for Rheumatologic Disease Cure Heats Up

 In June, we reported some of the latest findings on chimeric antigen receptor (CAR) T-cell therapy for rheumatologic conditions such as lupus. In this report, we take a look at what may be coming down the pike in this area.

At no time in the history of rheumatologic diseases has there been as much excitement as in the past couple of years, with the application of CAR T-cell therapy to systemic lupus erythematosus (SLE) and other conditions. Early results in several dozen patients have indicated that long-lasting drug-free remission after a single treatment is not only possible but is commonly achieved (84% of 145 SLE patients included in a recent review). This, obviously, has prompted optimism that actual cures are possible for what have always been lifelong debilitating diseases.

Now, some researchers are suggesting that CAR T-cell therapy is just the beginning, and that, as currently formulated and administered, it could and should be replaced with other approaches that limit the side effects and improve the chances for permanent remission.

This was evident at the American College of Rheumatology's (ACR) annual meeting in October, where some of these follow-on technologies were discussed and new data presented.

One session in particular sought, on one hand, to splash some cold water on the excitement surrounding CAR T-cell therapy, while on the other, offering a glimpse at how other cell-based treatments could improve on it.

Dark clouds had already appeared on the horizon for CAR-T. In May, the German group that pioneered the treatment in rheumatic disease reported on a troubling syndrome they dubbed "local immune effector cell-associated toxicity syndrome" or LICATS. It's a reaction to the dramatic depletion followed by reconstitution of B cells that is the therapy's main goal, in which "cleansing of immune cells" from organs affected by autoimmune disease leads to "transient worsening" of functioning in those organs. In their analysis, out of 39 patients treated with CAR T-cell therapy, 30 showed the syndrome to some degree, and in three it was severe enough to require hospitalization.

Other adverse effects noted with CAR-T treatments include cytokine release syndrome (CRS) in which the newly activated T cells release a flood of cytokines that can cause flu-like symptoms; the interleukin-6 inhibitor tocilizumab (Actemra) is often used to keep it under control. CRS is definitely distinct from LICATS, the German group asserted, citing the latter's localization and exclusive involvement of organs previously affected by the autoimmune disease in the patient.

And related to CRS is immune effector cell-associated neurotoxicity syndrome (ICANS), in which the brain gets involved with neurological symptoms. Both CRS and ICANS can be fatal, though rarely.

In the aforementioned review of 145 lupus patients, 56% developed CRS with all but one at grade 1 or 2. ICANS was seen in four patients but, worryingly, it was grade 4 in one case.

At ACR, Joan Merrill, MD, of the Oklahoma Medical Research Foundation in Oklahoma City, walked attendees through these and other problems with CAR-T treatments as currently practiced and that may turn up if they come into wider use.

For starters, she pointed out that standard CAR-T therapy involves a lymphodepletion regimen with cyclophosphamide and fludarabine, both very toxic chemotherapy agents. Infections can occur during this period of immunosuppression. About 8% of patients in the SLE review did, in fact, develop serious infections.

Merrill was also somewhat skeptical that LICATS is not actually a mild lupus flare, given that the symptoms and lab findings are so similar. "I'm not sure the case has been made" that LICATS is indeed a novel syndrome, she said.

Still other drawbacks with current CAR-T technologies include the laborious patient-specific process and associated high cost and the potential for production failure, she noted. She did acknowledge that some new approaches could make CAR-T treatment easier and more accessible, pointing to the September 2025 report on an in vivo process, in which patients are injected with lipid nanoparticles carrying genetic instructions for reprogramming patients' T cells.

This and other alternatives to "original" CAR-T therapy have more potential for lower cost, off-the-shelf products, more consistent efficacy, and less toxicity, she said.

Expanding on the potential for other "immune reset" approaches, Maximilian Konig, MD, of Johns Hopkins University in Baltimore, followed Merrill to the ACR podium to discuss more precise and presumably less failure- and toxicity-prone technologies, which are still in the earliest phases of development.

One of these is chimeric autoantibody-receptor (CAAR) T cells. Instead of destroying a patient's entire complement of B cells, why not just target those that produce the autoantibodies at the root of SLE? He pointed out that "it's unknown," and unlikely, that "global reset of the B cell compartment" is needed to stop the SLE disease process. Pathogenic B cells are identifiable because they express autoreactive receptors, allowing them (in theory) to be targeted by modified T cells. As early as 2016, Konig observed, researchers had been looking at this approach as a treatment for pemphigus, though it didn't work out in clinical testing.

Another more targeted approach is to modify T cells with chimeric auto-antigen receptors. Studies in the cancer sphere have shown that CAR T-cell therapies aren't very effective when the targets have low antigen densities. Using autoantigen receptors eliminates this problem, Konig said: T cells modified in this way use the autoantigen to latch onto autoreactive B cells and then kill them. Antiphospholipid syndrome is one disease that might be especially amenable to this type of therapy, he said.

Still another promising way to distinguish rogue from normal immune cells in autoimmune disease is to target a specific B cell idiotype dubbed 9G4, which is "innately autoreactive," Konig explained. In animal models and experiments with human blood samples, CAR T cells engineered to target 9G4 idiotype cells destroyed them completely while leaving normal B cells alone.

And that's not all -- particularly, it's not just B-cell driven diseases for which cell-based therapies could be practice-changing.

During the ACR meeting's late-breaking abstract session, Minna Kohler, MD, of Massachusetts General Hospital in Boston, presented interim results from a first-in-human clinical trial of regulatory (as opposed to cell-killing) T cells, or Tregs, modified with CAR technology as a treatment for rheumatoid arthritis (RA). This was commercially sponsored by California-based Sonoma Biotherapeutics, which hopes to develop patient-specific Tregs to treat a variety of conditions including inflammatory bowel disease and celiac disease as well as RA.

The idea here, Kohler explained, is to target the citrullinated peptides that accompany and help drive RA and other inflammatory rheumatic diseases. Six patients have been treated, of whom four have shown at least 50% reductions in swollen/tender joint counts 4 weeks after dosing. The treatment appeared more effective with the bigger of two doses tested so far; three more patients receiving a third, higher dose are still being evaluated. No safety concerns have appeared thus far.

While results after 4 weeks were fairly impressive, symptoms appeared to rebound in several patients with follow-up to week 12; 48 weeks is planned. Consequently, the results might be best viewed as proof of concept with more refinement needed to make a marketable product.

https://www.medpagetoday.com/rheumatology/generalrheumatology/119229