A. Lutterotti, S. Yousef, A. Sputtek, K.H. Stürner, J.-P. Stellmann, P. Breiden, S. Reinhardt, C. Schulze, M. Bester, C. Heesen, S. Schippling, S. Miller, M. Sospedra, R. Martin. Induction of immune tolerance by autologous peptide-coupled cells – a phase I trial in relapsing-remitting and secondary-progressive multiple sclerosis patients.
Objective: The aim of this first-in-man trial was to assess the feasibility, safety and tolerability of a novel tolerization regimen in MS patients, that employs 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).
Methods: An open label, single center, dose escalation study was performed in nine MS patients (7 relapsing-remitting and 2 secondary progressive), EDSS 1-5.5, who were off-treatment for standard therapies. All patients had to show T cell reactivity against at least one of the myelin peptides used in the trial. Neurological, MRI, laboratory and immunological exams were performed to assess the safety, tolerability and in vivo mechanisms of action of this regimen. We followed the overall patient immune response as well as responses to myelin antigens prior to and following the administration of peptide-coupled PBMC.
Results: Administration of antigen-coupled cells was feasible, had a favorable safety profile and was well tolerated in MS patients. Compared to the pre-treatment observation period there was no increase in clinical and MRI parameters of disease activity by this regimen. Patients receiving the high dose (>1x109) of peptide-coupled cells showed a decrease in antigen-specific T cell responses following ETIMS therapy.
Interpretation: The first-in-man clinical trial of autologous peptide-coupled cells in MS patients, establishes the feasibility, tolerability and safety of this novel therapeutic approach.
The problem with all current MS treatments is that they are not very effective and have side -effects or they are more effective but have more serious side-effects, This is because these treatments remove part of the immune repertoire that is used to fight infections and cancers. The only thing that gives the immune response its specificity is the target recognition receptors on white blood cells. So if you could only target the immune response that is causing the disease and leave the rest of the immune system intact you would have a treatment that works but would have essentially no side effects........ The Holy grail of Treatments in Immunology.
OK sit in your seats because I seldom enthuse, but if this study works to the author's plan it is a CURE to autoimmunity and could be the end to relapsing MS. If you stop relapsing MS you could stop MS, if you start early enough.
That's the plan, now to bring you down to earth. I would say it is half the cure or maybe a third as I will explain. The other half has already been tried in MS and it is safe. If this half is safe, which appears to be the case, you put the two halves together and relapsing MS is gone for good maybe to a single treatment with no side effects.
Why do I think that this could happen because I have seen this happen in the beasties, many, many, times
Many years ago when I was a PhD student I stated looking on antigen-specific tolerance induction. This means that it is a way of specifically turning the immune system off such that it no longer responds to your target of interest but does not interfere with the function of the rest of the immune system.
I was working on skin diseases in guinea pigs and found that if I put the sensitizing chemical on cells, it could induce immune tolerance (non-responsiveness) against skin disease. If I injected them intravenously. However it sensitized to disease (caused skin reactions) if I put them under the skin. The cells did not have to be alive they were just acting as a carrier that made the sensitizing chemical hang around for long enough.
This had been also been shown in mice by a guy called Henry Claman and another chap called Steve Miller. It is funny that both Steve Miller and I moved onto working on models of multiple sclerosis.
People in Steve Millers lab showed that if you stuck the proteins that you use to induce disease onto white blood cells and inject them into the blood of mice it stopped you from inducing disease. It even worked if you had already sensitized the mice to get disease and so worked in a therapeutic context. This is the basis for the trial.
Now in mice you usually know what the the inducing protein or protein fragment is. This is because this is what you use to cause disease in the first place, so if you induce disease with a protein fragment (a peptide) and then you inject that fragment intravenously it can inhibit T cell-driven autoimmunity. This is a very consistent finding throughout immunology, so there are no special tricks. It is a fact of biology.
In MS you do not really know what the immune response is against (I would say it is different from each individual and it changes as disease evolves, as it is with each individual mice strain. I would also say myelin basic protein would not be high on my agenda) so you have to make educated guesses.
In this study they have plumped for fragments of myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) and then fixed them onto the white blood cells. They used fragments of about 20 amino acids long because they are easy to make as you can synthesise them. It is possible that they do not induce antibody responses in contrast to the full protein (about 300-400 Amino acids long) and some of the proteins such as PLP are very difficult to make because they are very insolbule.
They then injected them into the blood of MSers who have immune responses to at least one of the fragments. These were injected into the blood of MSers and it did not cause exacerbation of disease which is the safety concern and luckily they have not caused any strokes, which could be a problem if the cells clumped.. It appears to have inhibited the T cell response, which is is the working mechanism for the therapy. so job done this could be a cure for the autoimmune aspect of MS. This is why this is exciting. The prospect
Let us see how the seven RRMSers do in the future
Now I will give you my view (could be wrong) of the challenges.
- The treatment is unlikely to work for non-gadolium enhancing/relapsing PPMS/SPMS. Why? This approach has failed in non-relapsing progressive EAE, where is it is essentially 100% effective against relapsing EAE, more on that later, and intravenous myelin basic protein (which contains all the peptide fragments of MBP) has failed in secondary progressive MS already.
- The peptide fragments that cause the disease will be different for different individuals and this may change as disease evolves. If the peptide fragments that cause the disease are not in the cocktail stuck to the white blood cells it will not work. If the peptide fragments are not the dominant driver of disease it may be less effective or not work.
- Now Dr Miller has reported that this approach induces what ever mechanism of action was dogma at the time of the experiment and includes CD8 T suppresser cells, Anergy-cell unresponsiveness, CD4 Th2 suppression and T regulatory cells etc. However, in virtually every immunologists hands the mechanism is specific to the target injected intravenously. So if it is not there in the cocktail of fragments then the approach fails.
- You probably cannot use a gemish of brain antigens as you can in animals. Use of human brain contains all possible targets. But as a gemish it has problems because of the fear of passing on human brain disease such as human mad cow disease. This has the advantage that you do not have to know the causing fragment you just give the immune system every thing and it works out what is interesting. On the plus side if you are lucky and control the dominant immune response it can be active despite the presence of autoimmunity to other minor targets.
- The problem may not be caused by autoimmunity, but we know it is an immune problem because relapses respond to immunomodulators. However, MS may not be a problem of autoimmunity to myelin antigens. If this is the case the approach will not work because the wrong peptides have been selected. There is another study that is using the intravenous approach against a non-myelin antigen which is ready for phase II already.
- They are injecting the target into an established immune system. This approach works quite well when the individual is not yet sensitized but is does not work as well as it should when the immune system has already become sensitised, which would be the cause when using in MS. Therefore, it may not work or give you a partial answer such that it works for a while and then disease returns
- We (Team G) believe that they should deplete the T repertoire before delivering the the intravenous target. This should be done when the immune cells are recovering from the depletion and it causes a re-education of the immune cells such that they are no longer self aggressive. However depletion of immune cells in MS has already been done and this approach is safe so if you put this current approach with the deletion event you can make the two approaches, which are not optimally effective when used individually and completely stops relapsing disease when used in combination.
Why is this exciting because it is the most robust and simplest way of stopping autoimmune disease in our hands.
As I have said before over 70% of EAE studies give the agents before disease is induced does this approach work? Yes but who cares this has no relevance to MS
Does the approach work after sensitization and before disease onset? Yes but who cares this has minimal relevance to MS. Less than 1% of studies in EAE administer the drug after the first attack. Very, very, very few after two attacks and none except ours after three attacks. What can this combination treatment do.
Number of Animals with subsequent Attacks
Timing of treatmet Placebo Treated
After 1 attack 36/36 1/35
After 2 attacks 21/21 0/8
After 3 attacks 37/48 0/66
These experiments have been repeated in many, many more mice and besides the odd failure we have not seen a return of relapsing disease. However, progressive disease continues once sufficient damage has accumulated. This gives the advantage as a treatment and also allows us to generate damage, stop relapsing autoimmunity and then look at repair.
4= hindlimb paralysis 1= paralysed tail. The results show the mean of a group of mice with EAE. Depletion was given on day 27 after the first attack and intravenous myelin-stuck on cells was given one week later.
Team G get are investigating this approach in humans but if we know the delivery of myelin antigens is safe, it will help in the translation of the approach.