Disease-Modifying Therapies (DMT) and the Immune System


Dr Schmierer introduces the disease-modifying therapies (DMT) that are available for patients with MS and their impact on the immune system.

Klaus Schmierer, MB BS, PhD, FRCP: Talking about disease-modifying treatments, there are fundamentally 3 groups we can separate. First, the so-called immunomodulators. This is the type of drug that was first licensed and that includes interferons, beta interferons, and Glatiramer acetate. These can be separated from the cell traffic agent or anti-cell traffic agents, which there are mainly 2. So there’s on the 1 hand, natalizumab, an antibody that is a monoclonal antibody that is being infused every 4 to 6 weeks preventing immune cells of the adaptive immunity [from] entering the brain. With a different mechanism of action, there are the S1P [sphingosine-1-phosphate] modulators that prevent trafficking into the brain essentially by removing the cell type, or relatively removing the cell type from the bloodstream and restricting them to lymph nodes. Then there’s a third class of drugs, which are cell-depleting therapies, that includes the drugs like rituximab, ocrelizumab, cladribine, or alemtuzumab. These compounds are targeting mainly B-cell subsets and I think it is important to note, for these drug types, that they can be separated from those that are being [used] regularly. So these are B-cell indicator, ocrelizumab, ofatumumab, and maybe in the future drugs like obinutuzumab, [INAUDIBLE]. Then, on the other hand, the immune reconstitution therapies. First, alemtuzumab which has been around for quite a number of years now, 2014 first licensed, and cladribine or oral cladribine—Mavenclad. These are generally the types of drugs that we have available at the moment.

When we’re looking at the current understanding of how disease-modifying drugs work and can look at the risk that is associated with that, we should first look at the fact that the drugs that we are using are mainly focusing on the adaptive immunity. So these are B cells and T cells as opposed to macrophages and dendritic cells—cells that belong to the innate immunity. Through particularly the human experiments, or clinical trials, we have pretty good evidence that those cells that are driving the immune activity, targeting the tissues in the brain, that are essentially leading to symptoms associated with MS [multiple sclerosis], are in the B-cell pool. Now, when we are relatively selective depleting B cells, such as with ocrelizumab, ofatumumab, but also mainly with cladribine, then we’re obviously removing or we’re leaving out other cell types or depletion of other cell types that may be associated with safety aspects of these drugs.

What is important is that for some of compounds, although the main target is the adaptive immunity, these compounds do not only act on adaptive immunity. An example is alemtuzumab, which is an immune reconstitution therapy which very strongly depletes T and B cells. It also has an impact on the nonadaptive, innate, immunity and that obviously contributes to particularly the early phases after it has been given to the risk of bacterial infections that is associated with the drug. That then subsides because in immune reconstitution therapies you give a brief spell of drug and then you get the depletion and that recovers over time.

We know that with most compounds that are acting on the immune system in MS, perhaps other than the immune modulators that I mentioned earlier, that there is an increased risk of opportunistic infections. Opportunistic infections, we know, for example, in natalizumab is a prime example. A drug that prevents access of T and B cells to the brain that also affects the normal immune cell trafficking. Although it is a low level of trafficking, but it is important in order to keep opportunistic infections at bay. But if that fails [this system] we can expose patients to the risk of PML [progressive multifocal leukoencephalopathy] so JC [John Cunningham] virus of which about 50% to 60% of the population harbor in their bodies. They are at risk for this.

This transcript has been edited for clarity.

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