Tolerance-Directed Immunotherapy: Future of MS Treatment?

Pauline Anderson

May 29, 2014

DALLAS — It may take some time and require overcoming certain hurdles, but the future of multiple sclerosis (MS) management may lie in delivering therapies that make immune cells tolerant of specific antigens.

These "tolerance-directed" immunotherapies could eventually provide a safe, cost-effective, and highly efficient alternative to current approaches to MS treatments that suppress the immune system and inevitably lead to patients becoming more susceptible to infections, cancer, and other disorders.

Stephan D. Miller, PhD, Judy Guggenheim Research Professor of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, elaborated on the development of these precisely targeted immunotherapies in his opening lecture at the 6th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research In Multiple Sclerosis (ACTRIMS).

He is also a cofounder and member of COUR Pharmaceutical Development Company Inc, a nanobiotechnology company focused on the development of novel immune therapies using nanotechnologies based on the Immune Modifying nanoParticle platform.

As Dr. Miller explained, targeted tolerance-directed immunotherapies intervene in the autoimmune response, affecting only the pathogenic autoreactive T cells that react to a specific antigen. Such therapies reset those particular cells to actually avoid an immune response, rather than suppressing a response.

In the future, such new therapies may allow clinicians to shut down the underlying disease process instead of just controlling MS symptoms, said Dr. Miller, who has more than 30 years of experience in the field of autoimmune research.

New Way to Treat MS?

"We hope that our tolerance-directed therapy offers a new way to treat newly diagnosed MS patients to halt their disease in a safe and efficient manner by treating the root causes of the disease without the need to take a lifetime of immunosuppressive drugs and in a way that will avoid potential side effects, such as infections and increased rate of cancer," Dr. Miller told Medscape Medical News.

He and his colleagues have already proven the tolerance-directed approach to be safe and effective in a mouse model and, with a group of German researchers, have shown it to be effective in humans. The results of that published study of 9 patients with MS found that the tolerance-directed immunotherapy reduced the patients' immune system reactivity by 50% to 75% (Sci Transl Med. 2013;5:188ra75).

The drawback in that study, though, was that it used a method that involved extracting white blood cells, processing them to deliver myelin antigens so that the body would develop tolerance for them, and then reinfusing these treated white blood cells into the patients.

Dr. Miller and his colleagues are planning another trial of tolerance-directed immunotherapy. However, rather than using the relatively complicated and pricey extraction-processing approach, they hope to be able to deliver the therapy via biodegradable polymer-based nanoparticles: poly (D,L-lactide-co-glycolide) or PLG. It's the same technology used in absorbable sutures that dissolve after tissue heals.

"We are currently in the planning stages of this phase 1 trial using myelin antigen containing PLG nanoparticles in newly diagnosed MS patients," confirmed Dr. Miller, adding that his team hopes to carry out the study in collaboration with neurologists at the Multiple Sclerosis Center at Rush University Medical Center in Chicago.

If all goes well, the study should begin within the next 6 months to a year, said Dr. Miller.

This novel treatment approach has broad implications not only for the treatment of MS but also for a variety of other immune-mediated diseases, including type 1 diabetes and rheumatoid arthritis, and other conditions for which physicians want to manipulate the immune system, such as asthma, food allergies, and islet transplantation in diabetes. Immunologic tolerance, said Dr. Miller, is the "holy grail" for autoimmune diseases.

Broad Implications

Asked to comment on this approach, Corey Ford, MD, director, MS Clinic, and professor, neurology, University of New Mexico, Albuquerque, who introduced Dr. Miller's lecture, told Medscape Medical News that the idea of "tolerizing" the immune system has been around for a long time and that this is the mechanism by which the drug glatiramer acetate (Copaxone, Teva Pharmaceuticals) may be working.

"We have thought for a long time that MS may be triggered by antigens of some sort — we don't know what they are; maybe they're viruses or other environmental triggers — and that desensitizing the immune system to those could play a role in treatment."

Dr. Ford used the example of a patient who is allergic to penicillin. "You can desensitize that person to penicillin by giving him very small doses and gradually increasing the amount so his immune system becomes tolerant," he said.

Dr. Miller's tolerance-directed immunotherapy would in essence be "a more targeted way to desensitize a person with an autoimmune disease to the antigens" that might be triggering their disease, said Dr. Ford.

Dr. Ford agreed that there's still a lot of research needed to determine which antigens and what sequence of antigens are important.

The "good news," he said, is that the nanoparticles "are safe, can be given to humans, and are approved." And the fact that the framework or platform the antigen attaches to is biodegradable removes the worry about toxicity, he added.

"If you can make educated guesses about the right ones to use, maybe you have a treatment for a disease like MS and for many other conditions. This is a strategy that's a framework; it's not just a single disease-targeted approach."

Dr. Miller is cofounder and member of COUR PharmaceuticalDevelopment Company Inc, a nanobiotechnology company focused on the development of novel immune therapies using nanotechnologies based on the Immune Modifying nanoParticle (IMP) platform. The IMP particles are derived from Food and Drug Administration–approved, biodegradable polymer poly(lactic-co-glycolic-acid) that, when modified and built using proprietary IMPtechnology, provide therapeutic relief in numerous inflammatory conditions.

6th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research In Multiple Sclerosis (ACTRIMS). Opening Lecture. Presented May 28, 2014.

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