Future Goals for CAR-T in Autoimmune Disease

Georg Schett, MD

Over the past few years, chimeric antigen receptor T-cell (CAR-T) therapy, which originally got its start in oncology, had become a burgeoning area of interest for the treatment of autoimmune disease. With a large number of new clinical trials having launched in 2023 and 2024, the field is rapidly evolving.

CGTLive® recently reached out to Georg Schett, MD, vice president of research and chair of internal medicine at the University of Erlangen – Nuremberg, who served as an investigator on the earliest CAR-T trial for autoimmune disease, to ask about what he sees as the future of the field. Schett went over the lessons learned so far from the early studies and areas of potential innovation that will be of interest going forward.

CGTLive: Can you give some background about CAR-T therapy in autoimmune disease?

Georg Schett, MD: Basically, CAR T-cell therapy has been developed in oncology to allow a deep B-cell depletion and it has been used in refractory patients with B-cell lymphoma and leukemia. It has brought patients who suffer from these severe hematologic malignancies into long lasting remission. The idea in autoimmune diseas is that a deep B-cell depletion could abrogate the autoimmune clones and could potentially lead to cure of autoimmune disease. Therefore CAR T-cell therapy targeting B-cells was introduced in autoimmune disease 3 years ago. So far, only a few patients have received CAR T-cell therapy for autoimmune disease. However, the data so far look very compelling. It is possible that the majority of patients receiving a single infusion of CAR T-cells can enjoy a drug-free remission for several years. We think that this drug-free sustained remission could ultimately lead to cure in some of these patients.

Can you discuss some of the developments that have occurred in this field in the past year or so?

It's of the utmost importance next to efficacy, which means reset of the immune system by deep B-cell depletion, that CAR T-cell therapy is also safe. The key concern in safety of CAR T-cell therapy is cytokine release syndrome and also neurotoxicity. So far, the data look pretty convincing that the risk for higher grade cytokine release syndrome and neurotoxicity is very low in CAR T-cell treatment in autoimmune disease.

The challenge is that autologous CAR T-cell therapy, which is currently most widely used, is technically challenging and needs manpower and a GMP facility to produce. Therefore methods actually to improve that CAR T-cell production are very important. For instance, there are trends to shorten the process of CAR T-cell manufacturing ex vivo, to use less space and less resources, and to allow more in vivo proliferation of CAR T-cells—so giving them earlier, back into the circulation of the humans. That's a very interesting development, which probably will increase also the scalability of autologous CAR T-cell therapy in humans.

Another approach is the so-called allogeneic CAR T-cell therapy, where actually stock of CAR T-cells is produced from a healthy donor, made hypoimmunogenic, and then can be used as a kind of off-the-shelf product. However, this approach has not been widely introduced yet into autoimmune disease and we will see how its efficacy can compare to autologous CAR T-cell therapy

Have there been any big lessons learned so far?

There are several products in clinical trials in autologous CAR T-cell therapy, which mostly target CD19, a surface marker which is specific to the B-cell lineage, but not actually expressed in the plasma cells—that would allow actually to deplete the B-cell lineage without touching the long-lived plasma cells, which are important for immune cell memory.

Now these products have also been introduced in human autoimmune disease, particularly in lupus, but also in myositis and systemic sclerosis, and there seems to be a very consistent efficacy among these products and also a consistent low safety concern in these products. So currently, most of these trials are phase 1 trials looking at the safety of CD19 CAR T-cells in autoimmune disease. If the safety is good, they will move to larger trials. I think we should not imagine that cellular therapy has similar trial sizes like conventional therapies like antibodies. When we look at oncology, CAR T-cell trials are rather small, often single-armed and are going to very resistant disease, and they have shown efficacy there. So we can expect that actually, phase 2 and phase 3 trials will still have a limited size, but are very focused in the recruitment of severe patients.

Do you think CAR-T will eventually move to earlier lines of treatment for autoimmune disease?

If CAR T-cell therapy provides a good safety profile, then I think CAR T-cell therapy could be an interesting approach to treat severe patients earlier, without the necessity to fade multiple drugs, which is of key concern regarding tissue damage and organ damage. So it is of some interest to move CAR T-cell therapy earlier in certain patient groups. Imagine you can abrogate the whole disease with a single infusion and do this early and prevent organ damage. I think that concept is very appealing. At the moment, I think we are not there because [earlier on] data on safety were basically not present, but now [those data] are actually coming up more and more. So at the beginning, actually, the therapy was limited to very resistant patients, but I think the concept to move earlier, if safety data look good, which they do so far, is extremely appealing to prevent organ damage.

This transcript has been edited for clarity.

Relevant disclosures for Schett include Bristol-Myers Squibb, Cabaletta, Janssen, Kyverna Therapeutics, and Novartis.