Bench-to-Bedside (and Back) Pays Off in Multiple Sclerosis Research


by Brenda Patoine

May, 2008

An Interview with Steve Hauser, M.D.
Professor and Chair, Department of Neurology
University of California, San Francisco

 

Q: You recently reported evidence from a clinical trial that suggests rituximab (Rituxan), an FDA-approved drug used to treat lymphoma and rheumatoid arthritis, may offer an important new therapy for people with multiple sclerosis. Rituximab targets B cells, whereas all other MS therapies target T cells, long considered the primary culprit in MS. What does this work suggest about the pathogenesis of multiple sclerosis?

A: This represents a paradigm shift in our understanding of what triggers focal inflammation and the acute flares and attacks in multiple sclerosis. It puts B cells at the center of the scheme.

It is really thrilling to have what could be a potent new treatment for relapsing MS. Whether this will be the case or not will obviously depend upon the longer-term phase 3 studies, which will tell us whether the drug is efficacious with repeated courses of therapy and if the safety profile seen in this study remains favorable over the long term. But there is no question that these results demonstrate that B-cell involvement is really central to the inflammatory phase of MS.

What’s most exciting to me about this work is that it illustrates beautifully how critical it is to test our ideas about multiple sclerosis in real people. Models of the disease have been enormously informative in directing our thinking about the cause of MS and in driving the wave of therapies that we now have. But ultimately, any basic science ideas related to MS must be informed by the testing of those ideas in people with MS. That’s where the rubber meets the road. That’s where the concepts either have validity and relevance to people living with MS or are merely biologically interesting but not clinically relevant.

Q: What led you to want to test a B cell-targeted therapy, when the majority of MS therapeutics research was focused on T cells?

A: It’s taken nearly 20 years of research to get us to this point. Two lines of evidence, from animal models and people with MS, led us to zero in on B cells. The first was the demonstration by our group in San Francisco, as well as by a group in Europe, that the demyelination seen in an animal model of MS that we had developed to better replicate the human disease was mediated by autoantibodies that were deposited on the surface of the disintegrating myelin membrane.

We then moved from the animal model back into human tissue and demonstrated, with Cedric Raine at Albert Einstein [College of Medicine], that a similar phenomenon was at play in human MS plaques. Based on that observation, others subsequently were able to elute the specific auto- antibodies from human MS tissue.

Armed with those twin discoveries—that autoantibodies were required to create a truly MS-like lesion and that autoantibodies are present on degenerating myelin lesions in people with MS—we went to Genentech, which had developed this drug, rituximab, which was active against B-cell lymphoma. Rituximab was and still is the only FDA-approved therapy that targets B cells selectively. We were interested in it because B cells are in the cell lineage pathway responsible for autoantibody production: they are progenitors for plasma cells, and plasma cells make antibodies. We didn’t have a therapy against plasma cells, but with rituximab, we had one against B cells. I presented our data, both in the animal model and in MS tissue, to Genentech and suggested that we explore whether rituximab would be effective in MS, based on the hypothesis that knocking out B cells would ultimately knock out the autoantibodies we were targeting.

I think that Genentech was rightly skeptical of this hypothesis, and it took some time to convince them. The question was, would a treatment that was so downstream of the autoantibody—targeting the B cell but not the plasma cell—be effective? But persistence paid off and Genentech made a major commitment. In retrospect, they gambled and embarked on two major trials [the second is in primary progressive MS; data will be unblinded in late spring 2008].

Q: Were you surprised by the clinical trial results?

A: The big surprise was that the beneficial effect was so rapid. We had originally planned for a study with re-treatment and longer follow-up, but the FDA wouldn’t permit this. They asked us to design a shorter study, so we had to set the primary endpoint at six months with follow-up for one year. We were concerned that this would not be enough time to show a clinical benefit, because we not only wanted to deplete B cells and plasma cells, but ultimately to deplete autoantibodies, which we knew would take some time.

When we saw that the beneficial effect seemed to be almost immediate, this was as stunning as the positive result itself. It means that the beneficial effects of rituximab are almost certainly due to a direct effect on the B cell itself, and not to an effect on the autoantibodies.

Q: How does this clinical finding impact basic science research in MS?

A: What I love about the rituximab data is that it not only teaches about the validity of our laboratory models of the disease, but it also gives us new and surprising information that we can then take back to the laboratory. Based on this work, we now know that B cells are absolutely essential to MS pathogenesis. Now, we need to go back to the laboratory to understand why.

There is some recent B-cell data that really is quite exciting, showing that B cells may work in lymph nodes by picking up immune complexes from macrophages and transporting those immune complexes to the medulla (the middle) of the lymph node, where they are then transferred to dendritic cells for presentation to T cells. So the benefits we’re seeing with this B-cell therapy may relate to interference with this role B cells play in activating T cells.

We also know, based on beautiful preliminary work by others, that when B cells return after they’ve been ablated by rituximab, they are less inflammatory. This suggests they may be reprogrammed. We need to explore all of these research avenues further. We need to understand why these cells appear to be at the center of the genesis of MS attacks.

Q: You have been an advocate for improving opportunities for and engendering the next generation of physician-scientists. Why should the public care about there being enough of this cross-breed of clinician and medical researcher?

A: In some ways, I think the rituximab experience is a poster child for why a cadre of clinician-scientists is important in the healthcare arena. Clinician-scientists are focused on bringing ideas from the laboratory to the clinic and then pollinating the laboratory environment with insights and questions that can only be obtained from bedside contact with real patients.

If we are going to make progress against the most complex common diseases, it is essential that we reconstitute each generation of clinician-scientists. We don’t need many; maybe 750–1,000 a year. But this is a group under threat. Those of us with gray hair are concerned that we are not bringing in enough ambitious, smart, and creative newcomers to the field of medical science.

Among the many issues that factor into this shortage are the impossibly long training period, which for laboratory physician-scientists can be 22 years after high school; the low salaries throughout this period; the debt that is incurred; the pessimism of senior faculty fueled by diminishing NIH funding opportunities; and the crisis in the healthcare delivery system, which makes the physician-scientist’s life on the clinical side of the academic medical center more difficult.

The joy of medical discovery is at a point that was unimaginable five years ago, yet we’re not turning our young people on to this career path in sufficient numbers, certainly not in the numbers the field deserves. It has made me respect my residents and other trainees enormously, because I think it takes a very special young person to pursue a career in medical research.