Exploring CAR-T for Autoimmune Disease

At the American College of Rheumatology (ACR) Convergence 2024 in Washington, DC, Georg Schett, MD, vice president research and chair of internal medicine at the University of Erlangen – Nuremberg, presented data from 2 studies evaluating CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies in patients with a variety of refractory autoimmune and rheumatic diseases. Specifically, these studies were the CASTLE basket study and a phase 1 clinical trial for CC-97540 (Bristol Myers Squibb).

CGTLive®'s sister site HCPLive® interviewed Schett on the conference floor to learn more about the promising safety and efficacy findings from these studies. He went over the data and also discussed the advantages of a new manufacturing process used to produce CC-97540.

HCPLive: Can you discuss the safety findings of CC-97540 CAR-T therapy?

Georg Schett, MD: That's a phase 1 study, and it's a safety study, so safety is the key end point in this study. Basically the study recapitulated very well what we know—that cytokine release syndrome (CRS) is mild to moderate—so there were no higher grade CRS cases in the study, which is very reassuring. There were no major infections in this study, which is also very reassuring. The bone marrow toxicity was also only very short because of the lymphodepletion, but there was no long term bone marrow toxicity. There was 1 grade 3 neurotoxicity, but that resolved within 24 hours and that's, I think, very okay. There was no other neurotoxicity. In fact, I think the bottom line is the safety of this phase 1 study so far looks very good.

How does next-generation manufacturing differentiate CC-97540?

Well, I think that's very exciting, in fact... Development of new technologies in CAR T-cells is very important, and this fast manufacturing is very exciting because it's only 5 days, and you actually need much fewer cells to be infused into a patient with this fast manufacturing method, with a similar expansion of the cells as with the original method. So I think that's very exciting and it's obviously also important if there's a shorter duration in the turnaround time and actually less need for production space, because it's just shorter. That's a big advantage for the field, I would say.

Can you discuss the CASTLE basket study and its findings?

CASTLE is an academic study and it's a basket study. It's a phase 1/2a study. CASTLE recruits lupus, myositis, and systemic sclerosis. CASTLE had actually recruited 8 patients and after 8 patients, when there was good efficacy and safety, it moved to the second phase, and that actually turned out to be positive. There was no major toxicity signal and a very good safety signal. This is essentially, at the moment, a positive study. We will see in total a 24 patient study. It's close to finishing off recruitment. Basically, we will see how at the end the data look, but everything at the moment looks good. I think what is really amazing is that all the patients who had the efficacy analysis after 6 months met the high quality efficacy end point. That means remission, major improvement in the myositis, or no progression with systemic sclerosis. All the 8 patients who had efficacy analysis, possible after 6 months, met the efficacy analysis and that was very exciting I would say.

What has been your experience investigating CAR-T therapies with autoimmune diseases?

We have now in our center treated more than 40 patients, and we have a single relapse so the relapse rate is very low. There have been occasional relapses reported in the field by other studies, but also with low dose CAR T-cell therapy because that was the starting dose. So this has to be interpreted in the right way, and I would say that relapses occur, of course, right? Nothing 100%. But so far, it looks that most of the people enjoy a drug-free remission for a long time and that's very exciting.

This transcript has been edited for clarity.

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

REFERENCES
1. Schett G, Littlejohn E, Kramer N, et al. A Phase 1, Multicenter, Open-Label Study to Establish the Preliminary Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of CC-97540 (BMS-986353), a CD19-directed CAR T Cell Therapy Manufactured Using a Next-generation Process, for Severe, Refractory Autoimmune Diseases. Presented at: ACR Convergence 2024; November 14-19; Washington, DC. Abstract 1753
2. Schett G, Müller F, Hagen M, et al. Safety and Preliminary Efficacy of CD19 CAR-T Cell Treatment in Rheumatic Disease – Data from the First Part of the Phase I/II CASTLE Basket Study. Presented at: ACR Convergence 2024; November 14-19; Washington, DC. Abstract 1750