Choosing the Right Patient Populations for CAR-T Clinical Trials in Neurologic Autoimmune Disease

Bruce Cree, MD, PhD, MAS

This is the fourth part of an interview with Bruce Cree, MD, PhD, MAS. For the first part, click here. For the third part, click here.

When novel therapies are being evaluated in clinical trials, selecting the ideal patient population for the studies is of great importance. This is especially true for chimeric antigen receptor T-cell (CAR-T) therapies, which despite their track-record of potency can carry substantial costs and risks.

In an interview with CGTLive®, 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, spoke about how clinicians working in autoimmune disease should make decisions regarding which patients may meaningfully benefit from participating in CAR-T clinical trials for neurologic autoimmune diseases. He emphasized that patients who have not yet tried standard-of-care options for their particular disease are unlikely to be the best choice for these trials, while patients with refractory disease who have exhausted available options may be a better fit, especially if their disease is likely related to the target of the CAR-T product in question.

CGTLive: What advice might you have for your colleagues considering CAR-T for neurologic autoimmune diseases?

Bruce Cree, MD, PhD, MAS: So the question is what are the autoimmune diseases that could potentially be tractable with CAR-T therapy? We have quite a few neurological diseases that we think of as being autoimmune and although we have better and better treatments for many of these conditions, some of them can be quite refractory to the therapies that we have. For example, with myasthenia gravis we've had broad spectrum immune suppressants used for many years and then more recently we've had complement inhibitors being used very successfully. But these very useful treatments come at a price: You interfere with complement, you wind up with potential for some serious adverse events: in particular, encapsulated bacterial infections, including meningococcal meningitis. So the treatment itself, although very effective, is associated with some side effects.

Furthermore, there are patients who are refractory even to these highly potent antibody-based therapies. There's a group of individuals in whom there is a great unmet need. People who have general myasthenia and are brittle and are refractory to our standard-of-care treatments are one particular group of individuals to consider for [CAR-T] therapies. There are patients, for example, with other autoimmune conditions, such as a relapsing or recurrent autoimmune encephalitis, which we believe is an antibody-driven cluster of diseases with different antibodies—that's potentially a great target because you're targeting CD19 B-cells that potentially are the antibody-making cells. We think it may be some of those early plasma cells that are the main producers of these autoantibodies and some of these are germane to the central nervous system, such as NMDA receptor encephalitis. CAR-T-based therapy might work incredibly well in that setting. You can think of many, many other examples. There are conditions that are inflammatory autoimmune disorders of the muscles—dermatomyositis, and so on—where you might think of a CAR-T-based therapy, as well. And there's chronic inflammatory demyelinating polyneuropathy.

Many of these conditions potentially are tractable so we should be thinking carefully about which ones are most likely to respond to a particular CAR-T therapy. The CAR-T therapy we’ve talked about a lot today is an antiCD19-directed CAR-T therapy, so which of these conditions are B-cell driven? Which are the ones that we think that B-cells have a critical role in? Those might be good conditions to start considering. 

I think the key thing, of course, because of the high costs associated with these therapies and the risks associated with immune depletion, we have to be really careful about selecting the right target population.We don't want to target people, say for example, with relapsing multiple sclerosis that are going to do great on Ocrelizumab or Ublituximab. Sure, that's low hanging fruit and I know some companies are very keen to go after that low hanging fruit. But do we really need to put those patients through a CAR-T-based therapy? Do we really need that? I would say no, we really don't need that. Don't target the patients that are doing well on [an approved] therapy or haven't been treated yet with the best possible [approved] therapy. The group to focus on—and this is just my opinion, of course—is the patients who have refractory disease for whom there really are no other therapeutic options. That's the unmet need. That's what you have to go after. And you have to be prepared to roll up your sleeves and do the hard work. There's a lot of green between here and the hole, but I think this angle of approach is going to be of potentially fantastic benefit to some patients. So we do have to be ready and willing to do the randomized control trials in order to prove beyond any shadow of a doubt that there's efficacy and that the safety profile for this therapeutic approach is going to be of long-term durable benefit for our patients.

This transcript has been edited for clarity.