Open-Label Studies Are Insufficient to Establish the Potential of CAR-T in Autoimmune Disease


Bruce Cree, MD, PhD, MAS, a professor of neurology and the clinical research director of the University of California San Francisco (UCSF) Multiple Sclerosis Center discussed the need for randomized-control trials for CAR-T in lupus and other autoimmune diseases.

Bruce Cree, MD, PhD, MAS, a professor of neurology and the clinical research director of the University of California San Francisco (UCSF) Multiple Sclerosis Center

Bruce Cree, MD, PhD, MAS

A September 2022 paper published in Nature Medicine, which covered a compassionate use study that treated 5 patients with systemic lupus erythematosus with a CD19-directed chimeric antigen receptor T-cell (CAR-T) product, generated substantial interest in the potential of CAR-T therapy to treat autoimmune diseases. Since then, a number of companies and academic institutions have kicked off additional CAR-T studies in a myriad of autoimmune disease indications.

In light of this ongoing flurry of activity, CGTLive® sat down with Bruce Cree, MD, PhD, MAS, a professor of neurology and the clinical research director of the University of California San Francisco (UCSF) Multiple Sclerosis Center, to get his view on misconceptions regarding the use of these engineered cell therapies for autoimmune diseases like lupus. Cree emphasized that although the early data from open-label studies may seem promising, a lot of doubt remains about confounding factors and more rigorous clinical trial designs will be needed to get a clear picture of the true potential of CAR-T in the autoimmune disease field.

CGTLive: What are misconceptions about CAR T-cell therapy in autoimmune diseases and how would you address them?

Bruce Cree, MD, PhD, MAS: After that paper in New England Journal of Medicine was published, there was tremendous enthusiasm around this—not surprisingly, right? You have conditions which are treatment refractory where patients are experiencing the withering effects of autoimmune diseases and then you have something that looks like it's just working incredibly well. Everybody gets really excited about it and thinks, “Okay, this is going to be the next best thing since sliced bread to come to autoimmune disease.”

Well, the problem with these small studies that are uncontrolled is we don't really have proof of efficacy. Things might look really good and we've gone down this path many times before with lots of other open-label studies. And the truth is, unless you have very well-controlled and incredibly well-designed clinical trials, you wind up with data that're difficult to interpret. This is one of the reasons that the FDA is so keen on carefully controlled clinical trials. You really need to be able to understand whether the intervention that you think is what's working is, in fact, the thing that's doing it.

So, what is it about CAR-T that there's some misconception about? Well, first off, I think a lot of people don't quite realize that there is, in fact, a conditioning regimen that CAR-T therapy requires. At least to date, patients are treated with some very powerful immune suppressants. They are treated with fludarabine and cyclophosphamide before they get the CAR-T therapies. That basically eradicates most of the lymphocytes and this creates an immunological space for the CAR-T therapies, once they are infused, to expand into. The question is, is there a therapeutic benefit of that profound immunodepletion to begin with? That's going to be a key question to address. Uncontrolled studies that are open-label don't do that.

READ MORE: Bringing Cell Therapy From Oncology to Autoimmune Disease Will Present New and Unique Challenges

One of the things that we really need to understand is how much of an impact that conditioning regimen is having on the outcomes of interest, regardless of the autoimmune condition that you're looking at. Whether you're looking at lupus or scleroderma, or multiple sclerosis for that matter, is the impact of the CAR-T the thing that's driving success? Or is it the immunodepletion regimen on its own? When we think forward to phase 2 studies, a critical question is going to be: “How do we know what the difference is between the CAR-T therapy versus the immunodepletion regimen?” The only way to do that is to immunodeplete everybody and then randomize patients to the CAR-T therapy. So everybody will get immunodepletion and then some people will have the CAR-T on top of it. That will tell us whether the CAR-T therapy in its total is better than the immunodepletion regimen. That's a very important question to address that has not been addressed and isn't really being discussed actively in the community at this point.

But that's not all. There's more to it than that because we're trying to position these CAR-T therapies as being somehow better than the monoclonal antibody. So now you really have to get down to brass tacks because we don't really know whether it's the CAR-T plus the immunodepletion that's doing it. What if you had the immunodepletion which is wiping out your lymphocytes and then you add an anti-CD20–directed monoclonal antibody on top of that? Well, would that work just as well as the CAR-T-based therapy? We don't know that question. Nobody's even talking about that right now. So now you're looking at a head-to-head randomized control trial, where everybody's getting immunodepleted and then you're comparing an anti-CD19–directed CAR-T therapy versus say, an anti-CD19 monoclonal antibody. It's going to be a tough study to do and it's going to be an expensive study to do because the development of CAR-T therapies is extremely expensive. And if it's only marginally better than an antiCD19 monoclonal antibody or no better at all, in the setting of everybody getting immunodepleted? Well, that's going to be pretty disappointing for the CAR-T therapy. As promising as these drugs are and as amazing as the technology is, we have a very, very long road and difficult road to navigate to prove that CD19 CAR-T therapy can substantially attenuate or even potentially cure autoimmune disease.

This transcript has been edited for clarity.

1. Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022;28(10):2124-2132. doi:10.1038/s41591-022-02017-5
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