CAR-T May Be Able to Target Pathogenic B-cells That Are Unreachable by Monoclonal Antibodies in Multiple Sclerosis

Bruce Cree, MD, PhD, MAS

Currently, several CD20-directed or CD19-directed monoclonal antibodies are used as treatment options for multiple sclerosis. Although these are effective in many patients and have been shown drastically deplete B-cells in peripheral blood, they are ineffective in a subset of patients.

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, is currently working on research aimed at exploring chimeric antigen receptor T-cell (CAR-T) therapy as a new option for patients with refractory multiple sclerosis. In an interview with CGTLive®, Cree discussed the rationale behind this approach and how it may be able to overcome certain limitations of monoclonal antibody treatments.

CGTLive: What is the rationale for using antiCD19 CAR T-cell therapy for autoimmune diseases?

Bruce Cree, MD, PhD, MAS: First off, CD19-directed CAR T-cells were developed as an antioncologic agent. This is a cell-based therapy, they are genetically modified T-cells from an individual—so they are an individual's own T-cells that have been harvested. They are then expanded and altered to specifically recognize a particular epitope on CD19. And then, when these cells are then reinfused back into the individual, they can direct an immune-mediated targeting of any cell expressing CD19. Now, CD19 is expressed on B-cells in the body. It's also expressed on vascular endothelial to some extent, but primarily the main target are B-cells. So not surprisingly, if you have immune cells attacking B-cells, they can eradicate the B-cells. This is why this strategy has been successfully implemented in lymphoma.

So we know that B-cells have a critical role in other autoimmune diseases including multiple sclerosis. And so there's interest in leveraging this technology to be applied to other autoimmune diseases. There was a recent study done in lupus patients—a small study with 5 patients that showed a dramatic and striking apparent beneficial therapeutic effect of treatment. So this has got people pretty excited. So these are patients who had lupus who were treatment refractory and seemed to respond to treatment with this CAR-T based therapy and so not surprisingly, other conditions that are autoimmune in nature in which B-cells have been implicated are being considered for further investigation with CAR-T therapies. We are very keen to see the application of CD19-directed CAR-T therapies in multiple sclerosis. Many other groups are also interested in this as well.

What do you see as the strengths of anti-CD19 CAR T-cell therapy vs other B-cell depleting therapies for autoimmune diseases?

When you when you think about depleting B-cells, you could just ask yourself the question: “Well, we already have monoclonal antibodies that do a spectacular job of depleting B-cells? We have CD20 monoclonal antibodies that are FDA-approved already for treatment in multiple sclerosis—3 of them: Ocrelizumab, Ublituximab, Ofatumumab. We have a CD19-directed monoclonal antibody that's approved for treatment in neuromyelitis optica spectrum disorder. So why do you need anything else? Well, the thing is, all of these treatments work incredibly well. And they work incredibly well in many, many patients—but not in everybody. There's a group of individuals, especially in multiple sclerosis, who have progressive disease and who when treated with an antiCD20 monoclonal antibody therapy may see some benefit for a short period of time—but then they go on and start progressing anyway. And so there is in fact an unmet need in patients with progressive multiple sclerosis, who are worsening despite treatment with antiCD20 monoclonal antibodies. The same applies to other autoimmune diseases. As good as these drugs are, they don't always work. And so that's the question when you have patients who have refractory disease who are getting worse despite your very best treatments: Well, what you do next?

And so the concept here is that there could be tissue-embedded, CD19-positive B-cells that are still actively involved in disease pathogenesis that are beyond the reach of monoclonal antibodies. These tissue-resident cells may not be easily depleted by a monoclonal antibody. When you infuse the monoclonal antibody, predominantly it's in circulation. And, not surprisingly, when you measure and look for the effect of the antibody in circulation, you see profound depletion of B-cells in peripheral blood. But those are only a fraction of all the B-cells in the body. There are B-cells that are, we think, resident within the central nervous system that would not be accessible to targeting by a monoclonal antibody in the case of multiple sclerosis. The same would apply to other autoimmune diseases. There may be B-cells deep within lymphoid tissues elsewhere in the body that monoclonal antibodies simply can't get to.

And so the concept here is with the cell-based therapy—since these are in fact the body's own T-cells that have been genetically modified—is that these cells will have access to areas of the body where there are B-cells that an antibody-based therapy can't get to. In multiple sclerosis, this is a very compelling story because we know when we look at the brains of multiple sclerosis patients at autopsy we do in fact see tissue-resident B-cells and T-cells within the brain, within the meninges, and in the perivascular spaces. We know that these [pathogenic B-cells] are present there and are in this privileged location where monoclonal antibodies simply can't get to—or can’t get to easily—and even if the antibody gets there, most of the antibodies kill B-cells through complement-dependent mechanisms. So not only do you need the antibody, you also need complement. And as you know, complement is primarily in circulation. You don't really see complement within the central nervous system. So a cell-based therapy that can cross the blood-brain barrier and get at these tissue-resident B-cells that are embedded deep within the brain and within the meninges has the potential to eradicate these cells. The question is: “Well, is that going to do something helpful for multiple sclerosis?” And we honestly don't know, that's why we have to set up the experiments. This is the hypothesis that we plan to test. We want to know whether these cells can cross the blood-brain barrier. That's going to be, of course, one of our first goals if we are able to launch these studies. We want to find out if the cells get into the central nervous system? And then the second question is, once they're there, are they able to eradicate B-cells? So we hope to be able to address both of these questions in a meaningful way in a study that we hope to begin conducting at UCSF in the near future.

This transcript has been edited for clarity.