Lessons Learned in Cell Therapy for Autoimmune Disease

David Porter, MD
Credit: Penn Medicine

CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy has made headway in the past few years as a potential new option for the treatment of autoimmune disease, with a number of new clinical trials having been launched in 2023 and 2024. To take a look back at the progress made, and what still needs to be done, CGTLive® reached out to David Porter, MD, the director of cell therapy and transplant at Penn Medicine, to get his perspective.

Porter discussed some of the key lessons learned in the past year, highlighting that in early trials, the vast majority of patients treated with CAR-T for autoimmune disease have achieved some type of response and have been able to come off of their standard immunosuppressive therapy. He also spoke about areas where more research is required, stressing the need for data from more patients and longer follow-up times.

CGTLive: Can you give some background about the current state of cell therapy in autoimmune disease?

David Porter, MD: I think in the last year there's been really exciting information and tremendous progress using cell therapy to treat autoimmune disease. It's been a logical endeavor. We know that many autoimmune diseases are caused by autoantibodies made by abnormal B-cells and many of these diseases can be treated by targeting B-cells with anti-B-cell antibodies or other immune suppressants. So I think it was logical to try and use CAR T-cells directed against B-cells, whether that be CD19-directed or even BCMA-directed CAR T-cells, for really profound, deep B-cell depletion, with the hope of then treating autoimmunity. There has been increasing data coming out over the last year showing it can be remarkably effective. In fact, the vast majority of patients who have been reported in the literature have at least responded, and the vast majority have been able to come off their immunosuppressive therapy, many in complete remission. So I think it's really been an exciting time for the field.

How would you say the field has changed in the past year?

I think there have been a lot of lessons learned. The data coming out is still really quite limited, and so I think we all have to have some caution. It's very small numbers of patients with very short follow-up. I think that is really a reason to pause and have a little bit of caution interpreting it. That said, the vast majority of the reported data describes just about every patient responding on some respects.

I think we have learned a lot. There is concern whenever you use CAR T-cells about toxicity in particular. That's a major issue, of course, using CAR T-cells to treat cancer patients. The unique toxicities are things like cytokine release syndrome and the unique neurologic toxicity.

It has been hypothesized that toxicity is likely to be more limited when you use CAR T-cells to treat autoimmunity, in part because the antigen burden is lower. When you treat patients with lymphoma or leukemia, they may have pounds of tumor with really, really high antigen burdens that you don't get in patients with autoimmunity. In fact, I think one of the things we learned is that toxicity may be more limited in patients with autoimmunity. I also think that clinicians are much better at dealing with the toxicity—in identifying early cytokine release syndrome and being able to intervene early—but I also think the risks look like they're lower than they are in patients with, say, far advanced leukemia or far advanced lymphoma.

What would you say are the major challenges right now, or areas where more research is needed?

I think tremendous amounts of research is needed. Right now, the data available is really on very small numbers of patients with heterogeneous diseases and with very short follow-up. At the very least, more patients need to be treated, we need to have a better understanding of the anticipated clinical outcomes, and we need longer follow-up. Are these responses sustained? Will patients ultimately have recurrence of their disease? There are reports of a number of patients who have had profound B-cell depletion, but in many cases, then recover B-cells, and as they recover B-cells, they recover a normal B-cell repertoire, without the abnormal or dysfunctional B-cell. So I think that that is really important. Does that mean these remissions are likely to be sustained over time? I don't think we know yet, but that is research that's going to have to be done.

We still need to address the toxicity. Patients who have rapidly progressive, life-threatening cancers, have a different risk-tolerance than, say, a patient who may have autoimmune disease. It's going to be very important to understand the toxicities associated with the T-cell therapy, including things like cytokine release syndrome and the neurologic toxicity, toxicities that might be associated, say, with profound B-cell depletion, both in the short run, but perhaps in the long run, as well.

I think there's a lot of concern about using the lymphodepleting chemotherapy, again, in a population of patients that aren't being treated for malignancy, aren't being treated for far advanced cancers. So can this be done with less lymphodepletion chemotherapy, with less intensive immune suppression, and can we manage the toxicity where the risk-benefit-ratio becomes really quite favorable? I will note that many patients with autoimmune diseases have long-term complications from the immunosuppression that they're on, long-term complications from disease activity, and these can be quite awful diseases. But again, it's very different than a patient who might be treated with a rapidly growing lymphoma, who may have weeks to live—then your risk-tolerance becomes very different. I think we will learn all that over the next year or several years—how much lymphodepletion is needed, what intensity of chemotherapy is needed, what are the ultimate clinical outcomes? What are the responses? Are they sustained and really, what are the short-term and long-term toxicities going to look like? I do think in the last year we're starting to get a sense that the responses are exciting and the toxicities so far have been manageable.

This transcript has been edited for clarity.