A Treatment Within

Therapeutics usually start this way: created outside the body and inserted. But researchers are experimenting with an opposite approach, where a patient’s own altered blood cells are used as a treatment for multiple sclerosis.

Administration of antigen-coupled cells to 10 people with relapsing or secondary-progressive MS was feasible, had a favorable safety profile, and was well tolerated, according to a team of international researchers who investigated the approach. In addition, they report that patients in the Phase I trial, which was published June 5 in Science Translational Medicine, showed signs of reducing immune responses to myelin.

To start, researchers used a single infusion of autologous peripheral blood mononuclear cells chemically coupled with seven myelin peptides (MOG1–20, MOG35–55, MBP13–32, MBP83–99, MBP111–129, MBP146–170, and PLP139–154). All patients had to demonstrate T-cell reactivity against at least one of the myelin peptides used in the trial. Each then received an infusion of their own carrier blood cells coupled with the peptides. They were observed clinically and via MRI for six months.

While treatment was well tolerated, researchers also noted those patients receiving the higher doses (>1 × 109) of peptide-coupled cells had a decrease in antigen-specific T cell responses after peptide-coupled cell therapy.

One of these researchers, Roland Martin, MD of the Institute for Neuroimmunology and Clinical MS Research in Hamburg and University Hospital Zürick, spoke with Practical Neurology about the study.

What should neurologists take away from this study?

The approach that was used in our study has a long-standing and very good track record in animal models. It works very well in animal models for several autoimmune diseases, including MS, prophylaxis of transplant rejection and severe allergies, prevents broadening of immune responsiveness to multiple auto-antigens (in animals; a process called epitope spreading), and was always safe in the animal setting.

Our study is really only the very first step, but the good tolerability and safety as well as the indication that the frequency of auto-reactive T-cells is reduced are very promising, and we hope to be able to go to the next step, i.e. a Phase IIa trial, very soon.

So, for neurologists the study is not immediately applicable in the moment but offers at least some hope that this approach (and others) will at some point be useful to re-establish tolerance in MS.

You selected seven peptides of myelin proteins that have shown high immune reactivity in people with MS. How were these seven selected?

The choice of peptides is based on over 20 years research on recognition of auto-antigens in MS patients, and these data come from multiple groups, including ours. The exact choice of peptides is mainly based on a study from my laboratory (J Immunol.;172(6):3893-904), in which we examined the antigen specificity of high avidity (those that recognize auto-antigen at lower antigen concentrations) myelin-reactive T cells. We and others later confirmed that almost all MS patients respond to at least one of these peptides very well in MS cohorts in Spain and in Germany, similar to the original study in the US (Snyder et al. 2007, NIH).

In the laboratory, these peptides are coupled by way of a chemical process to a patient’s carrier cells taken from their blood. Can you talk about this process?

The coupling of the peptides is done as follows: peripheral blood mononuclear cells are obtained from the patient by a leukapheresis (similar to a blood donation, but erythrocytes are given back to the patient). The cells are collected in a blood bag, and then under GMP conditions (clean room), the myelin peptides and a coupling agent (EDC; couples all molecules with free carboxy and amino groups covalently) for a certain period of time. Then the cells are washed, tested for peptide coupling, for sterility, removal of the coupling agents, before it is released for re-infusion to the patient.

The coupling process leads to inducing apoptotic cell death in the treated autologous cells, which are then infused and undergo cell death in the body of the patient. Death of autologous cells, which occurs in our body all the time in many tissues/cells, is a very strong signal to the immune system to not mount an immune response. The addition of the specific auto-antigens is then thought to induce specific immune tolerance by mechanisms that are reasonably well established in animal models but need to be confirmed further in humans.

Essentially, what led you to this study and what makes this treatment method intriguing? Why are you hopeful?

We had an unsuccessful but highly informative trial with one of the myelin peptides (but modified in two amino acid positions), which was published in Nature Medicine in 2000 (6(10):1167-75.). In this trial we saw an increase rather than decrease of disease activity, which provided direct proof in humans that myelin-specific immune cells are disease-relevant. After that trial and many discussions of what might have gone wrong and what one might use in the future, we identified the approach by S. Miller et al. as a particularly promising one and then decided to start that. The project was then started substantially after my leaving NIH and returning to Europe. We received almost $1.5 million from the German government and in a very involving process, due to the high regulatory requirements, we finally were able to perform the study in Hamburg.

You believe this is a feasible approach to take to larger trials, and that it appeared to be well tolerated. What’s next, and what needs to happen to fulfill that? What are your obstacles?

Next steps are to find a sponsor for the Phase II trial; we are currently working hard on that. As soon as we have public and/or private funding, we will conduct a Phase II trial probably in three centers. The major hurdles for that are, at the moment, that using ex vivo GMP-manipulated cells is too burdensome and impractical to “lift” this approach to broader use. To circumvent that we are adapting the process to non-GMP conditions, i.e. in a transfusion kit, that can be handled and prepared in a day hospital setting and thus could be relatively easily used in a broader patient population. The regulatory documents for all this are currently being prepared, and I am optimistic that we can move forward to larger trial soon—as soon as we have funding as a precondition.