Antigen-Specific Therapy for MS Passes Safety Test
Phase 1 study shows hint of immune tolerance to myelin
Scientists are reasonably certain that much of the early damage in multiple sclerosis (MS) results from misdirected immune cells destroying the myelin sheaths and injuring the underlying nerve fibers. An experimental approach to selectively turn off the attack on myelin has cleared a key hurdle: It appears to be safe in people, and there are hints that it may work to retrain the pathological white blood cells that assault the brain and spinal cord in MS while sparing the rest of the immune system.
In a small phase 1 study in Germany, researchers tested a way to teach a person's immune cells to ignore, rather than attack, the myelin coating of axons in their brains and spines. Blood samples from the three people receiving the highest doses of their own altered white blood cells showed a 50% to 75% reduction in reactivity to fragments of myelin protein. Two of the high-dose patients experienced exacerbations of symptoms and new lesions on brain images soon after the infusions, but they were similar to previous relapses and not believed to be caused by the experimental treatment. The results were published June 5 in Science Translational Medicine (Lutterotti et al., 2013).
"This is an important trial," said Gerald Nepom, M.D., Ph.D., an immunologist at the Benaroya Research Institute in Seattle, Washington, and head of the Immune Tolerance Network (ITN), an international group of researchers sponsored by the U.S. National Institutes of Health (NIH). "It's the first time this approach has been safely used in people. It's now possible to think about how to give antigens to people in a way that will tolerize the immune system." Nepom was not involved in the trial, but the ITN is in discussions with the authors to help plan a larger study of effectiveness within the next few years, if further safety testing goes well.
Outcomes of phase 1 safety studies are notoriously unreliable in predicting the fate of experimental therapies, but several news stories, including one at Foxnews.com, called it a treatment "breakthrough," echoing a press release from Northwestern University, where the protocol was developed and tested in mice. The tantalizing news coverage generated many inquiries from people with MS, the authors told MSDF, even though no one knows if the experimental approach will be effective.
The latest findings are better described as a scientific milestone in moving toward a more targeted and long-lasting treatment for MS than the current broad-acting disease-modifying therapies now prescribed for patients, the authors and other experts told MSDF. Current MS drugs walk a fine line between limiting the autoimmune attack on the central nervous system while at the same time avoiding compromise of the immune defense against infections and cancers. The stronger and more effective immune-modifying medicines to treat MS have greater risks of harmful side effects.
The opposite safety-efficacy balance has plagued the short history of antigen-specific therapy tests in MS. Either the experimental antigen worsened the disease, or it did nothing (Lutterotti et al., 2013). The concept of antigen-specific therapy involves identifying and targeting the few bad actors in the immune system that attack a person's own tissue. In MS, the wrongdoers are misdirected T cells that target the myelin coating of nerve fibers in the brain and spine.
Paradoxically, the clinical trial setbacks have helped advance the science that enabled the encouraging new safety study. Thirteen years ago at the NIH, for example, one failed phase 2 trial (Bielekova et al., 2000) provided convincing evidence that T cell responses to myelin protein fragments were important in MS, even if the injected peptides inadvertently made the disease worse. "After that failure, we went back to the drawing board," said Roland Martin, M.D., a neurologist and immunologist who oversaw the NIH trial. Martin, now at University Hospital Zurich, is corresponding author of the new paper.
The latest study smartly incorporates lessons from failed clinical trials and theories developed in animal models, as well as embedding detailed biological measurements important to subsequent studies, said Amit Bar-Or, M.D., a neurologist and immunologist at the Montreal Neurological Institute in Canada (who is an Accelerated Cure Project Scientific Advisory Board member).
For more than 30 years, scientists have known how to reset the immune systems of mice to stop T cells from reacting to certain antigens (Miller et al., 1979). The basic method involves isolating white blood cells from the animal, attaching the antigens to the cells, and transfusing them back into circulation. This technique induces tolerance to target tissues in several animal models of autoimmune disease, including experimental autoimmune encephalomyelitis (EAE), many studies have shown.
Since his original insight as a postdoctoral fellow, Stephen Miller, Ph.D., an immunologist at Northwestern University Feinberg School of Medicine in Chicago and a co-author of the new paper, has refined the tolerance-inducing technique in mice, figured out how it works (Getts et al., 2011), and developed a strategy to address a major complicating issue in applying this approach to people with MS. The problem is, no one knows exactly what sets off T cells.
"T cells do not see the whole proteins, they see small segments chopped up and presented to the T cell receptors as small molecules on antigen-presenting cells," Bar-Or told MSDF. "In spite of a lot of work, there is no consensus of target-specific epitopes. The feeling has been that there are different [T-cell] targets, not only across individuals but in one individual over time," a phenomenon called epitope spreading, described nicely in animals by Miller and his colleagues (McMahon et al., 2005), Bar-Or said. Evidence in animals and people suggests that inflammatory T cells may enter the central nervous system armed to attack one myelin peptide, but trigger a complex chain of events that sparks new attacks against other myelin fragments (Weiner, 2009).
For the new study, Martin turned to Miller to adapt the animal techniques to people. Previous trials tested a single myelin antigen, but the Miller protocol calls for attaching several different myelin antigens to blood cells with a certain chemical cross-linking agent, called EDC for short. The process kills the blood cells. In mice, when the dead cells are reinfused, they carry the antigens into the spleen, where they are cleaned out of the blood by an immune scavenger process that ultimately rebrands the antigens as nonthreatening. The approach "completely shuts down the disease prophylactically and therapeutically," Martin said. "And it prevents the immune response [in the brain] that broadens the autoimmune-reactive epitopes."
The latest study, called Establish Tolerance In MS, was conducted at University Medical Center Hamburg-Eppendorf. The team screened people with MS to find 10 participants whose T cells reacted to at least one of the myelin antigens in the test mixture, a cocktail of seven fragments from three proteins, myelin basic protein, myelin oligodendrocyte glycoprotein, and proteolipid protein. Previous studies by Martin and others had identified the seven peptides as common targets of autoreactive T cells in blood samples of people with MS (Lutterotti et al., 2013). One person dropped out of the study before the test therapy for reasons unrelated to the procedure. Of the nine people remaining in the study, eight were women. Seven people had relapsing-remitting MS (RRMS) and two people had secondary progressive MS (SPMS).
Researchers extracted white blood cells from each person, bound them to antigens, and reinfused the peptide-decorated cells in a single infusion. The process takes 4 hours, Martin said. The first six patients were selected with low disease activity. The researchers began with a low dose of 1000 antigen-coupled cells and gradually worked their way up to 1 billion cells. None of the patients showed a relapse during the first 3 months after treatment. The team increased the dose in three more patients with more active disease, testing 1 billion, 2.5 billion, and 3 billion antigen-coupled cells.
Patients generally tolerated the infusions well. Two of the final three patients had relapses of symptoms and lesion flare-ups on brain scans about 2 weeks after the infusion. These were consistent with previous relapses, and the investigators believed the cell therapy was not responsible. Three months later, the four patients receiving more than 1 billion antigen-coupled cells showed a decrease in antigen-specific T cell responses. All of them maintained a high reactivity to tetanus, an indicator that the rest of the immune system remained unaffected.
"Clearly, you cannot launch into a larger controlled study without this important initial step," Bar-Or told MSDF. "Safety is critical, but it's not particularly helpful to have something safe that doesn't work. The biological readouts from this study support moving forward with higher doses and a closer look at the efficacy signals."
(Bar-Or is a site leader of a phase 2b clinical trial testing a similar approach in people with SPMS. The study aims to prompt a vaccinelike immune response to eliminate, rather than turn off, myelin-reactive T cells. In the procedure, white blood cells are drawn, selected for reactivity to a group of myelin antigens, expanded, killed, and injected under the skin. The study is sponsored by Opexa Therapeutics in The Woodlands, Texas.)
Martin and his colleagues have designed a follow-up phase 2a clinical trial to be conducted at three sites. They want to test higher doses for safety and impact on disease activity in people with earlier RRMS. The researchers are seeking funding and have applied for European Union regulatory approval to conduct the study in Switzerland.
Ultimately, Nepom and others predict that regulatory, safety, and cost issues will favor tolerance therapy with biodegradable particles, rather than a person's own cells, to carry the antigens into the spleen. "In thinking about what the future holds clinically, it's a heck of a cumbersome procedure," Nepom said. "That kind of customized therapy is OK for proof of concept and the follow-up trial, but probably not for long term."
An alternative tolerance strategy was more recently developed by Miller and other collaborators. In EAE mice, antigen-coupled microspheres made of suture material prevented disease, inhibited established disease, and suppressed relapses caused by epitope spreading, Miller and his co-authors reported in a paper published online last November in Nature Biotechnology (Getts et al., 2012).
Based on other mouse studies, the clinical results of the tolerance therapy have implications for other diseases with an autoimmune component, such as type 1 diabetes. "This is a pivotal first-in-man trial and appears to show safety," Miller said. "The next step is to show that there are not additional safety issues, and at the same time show that the mechanism that worked in mice actually works in people." Then, he said, they can ask what to use, cells or microparticles.
Key open questions
- Will this approach build long-lasting tolerance to myelin protein antigens in people with MS, and will the tolerance have a therapeutic effect?
- Which antigens need to be included in a tolerizing regime for clinical use?
- Would the particles be a more effective strategy for clinical development, because of regulatory issues, safety, purity, and sterility?
The researchers and study were supported by an Alexander von Humboldt Foundation fellowship, the Gemeinnützige Hertie Foundation, the German Federal Ministry of Education and Research, the Cumming Foundation, and the Myelin Repair Foundation. A. Lutterotti, S. D. Miller, and R. Martin are listed as co-inventors on a University Medical Center Hamburg-Eppendorf patent related to the use of antigen-coupled cells in MS. The other authors declare they have no competing interests.