Friday, 12 October 2012

ECTRIMS: Half way to a cure of Autoimmunity?

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.

CoI: None. 
                                                  


32 comments:

  1. Wow. From Prof G's 'nothing groundbreaking' to a treatment which could be the beginning of a cure for RRMS!

    I have lots of questions but the most important first - how long before we could reasonably expect this approach to be developed and refined such that it would be available clinically? And shouldn't this be the target of major funding to accelerate such a promising therapy?

    ReplyDelete
  2. Wouldn't it make sense for Team G to collaborate with the team who have done this work to combine your T-cell depletion theory with theirs rather than work in isolation and possibly duplicate effort etc? Together you might just be the ones to cure MS!

    ReplyDelete
  3. When you say 'deplete the T cell repetoire' does this mean with something like alemtuzumab, or is it something else? And the new approach is it a one off chemically modified but ordinary blood transfusion- not stem cells?

    ReplyDelete
  4. Will this approach do anything to halt degeneration?
    Or will work only in early stage?

    ReplyDelete
  5. Will this approach do anything to halt degeneration?
    Or will work only in early stage?

    The earlier the better in the bottom graph the animals lost 16% nerves, that is probably becuase they lost this before treatment started in the placebo group at 80 days they had lost 40% nerves. Stop relapses stop nerve damage, but it does not prevent progressive disease, just as it appears immunosuppression does not stop progressive MS

    ReplyDelete
  6. And shouldn't this be the target of major funding to accelerate such a promising therapy?

    You would have thought wouldn't you. I would, but tell this to the scientific community!

    It they don't approve it it does get published or funded.

    The funders cannot fund it if the reviewers do not approve it.

    Immunologists did not like part of the message that MS is not all about immunology and it is not about mechanism so the community does not score applications like this highly. It works via multiple mechanisms...biology is simple yet complex. Go figure.

    Some little birds told me that one of the many applications was read by the authors of this abstract and that is when they got their idea to start this trial.

    We are currently self-funding to do some more work on this to try make it to a stage where we do not have to guess what peptides/proteins to do.

    What is the time frame well if in this study if they have money to do the next stage then there are a few years and then the phase III a few more years. I did not look if a pharma is behind this or not.

    There is another approach starting phase II so that is ahead

    We will see if they work in phase II. It they do they will not want to add the depletion step the question if they don't work is that the end?. Maybe for the people do the studies? The idea has been published for some time, the people just have to wake-up
    and put an extra arm in their studies

    ReplyDelete
  7. Wouldn't it make sense for Team G to collaborate with the team who have done this work to combine your T-cell depletion theory with theirs rather than work in isolation and possibly duplicate effort etc? Together you might just be the ones to cure MS!

    Maybe in the future there is not duplication at the moment.

    But there are problems with the approach. There is no need to use patient cells it adds an unecessary layer of complexity. You could put the peptides on a biodegradable bead.
    and they the approach would not need to personalised this could be batch made and make a cost saving and industrialise it.
    Peptides last in the circulation a few minutes the idea of sticking it on cells makes it hang round for longer adds a safety factor, but creates a liability. i.e stroke. The targets may not be the right ones either. The phase II will show this or not

    ReplyDelete
  8. When you say 'deplete the T cell repetoire' does this mean with something like alemtuzumab, or is it something else? And the new approach is it a one off chemically modified but ordinary blood transfusion- not stem cells?

    Yes something like and could be Alemtzumab. The problem here is humans take alot longer to repopulate their cells than mice.
    If there are no cells to re-educate then it won't work

    We are trying a chemical depletor in our trial. A company wouldn't give us another agent we wanted.

    Yes it is essentialy a modified blood transfusion not stem cells. In my opinion they are inert carriers and probably dead.

    It is interesting that if you give a blood transfusion of the donor cells before you give a kidney transplant it improves transplant survival. Why? In our humble opinion they are just putting a cell carrying the protein fragment used for target for rejection of the graft and then you are putting them in the blood. So their is your prove of concept.Interesting

    ReplyDelete
  9. Have a read of the concept look at the date.....Wasted years

    Pryce G, O'Neill JK, Croxford JL, Amor S, Hankey DJ, East E, Giovannoni G, Baker D. Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis. J Neuroimmunol. 2005;165:41-52.

    ReplyDelete
  10. A great paper, not had the influence it deserved judging by citation (a few sour grapes there!). As MD says it is chapter and verse on how to do these studies and another important conclusion is that neuroprotection must be part of the arsenal before we can talk about cures.

    ReplyDelete
  11. Yes a great paper without recognition.

    If many EAEers would care to digest this they may start to think differently. Still the vast majority of EAEers have never met an MSer and think the whole solution to MS is immunology. If many clinicians actually cared to take note they may not slag EAE off as much.

    Whilst I am ranting I may as well tell you the story of this paper (Above).It followed on from our depletion studies and we had the basis results in the late 1990's.

    We presented it at a meeting in France and I know a Swiss guy read the poster about a year later the same idea appeared in the Journal of Experimental medicine using sexy transgenic approach, which has nothing to do with actual disease. Originality dented...sure fire way of killing papers.

    However this suffered because there were loads of papers telling us how intravenous tolerance works. This was all done before sensitization. So if you showed something therapeutically relevant, so what no interest to scientists. Likewise no interest in funding so with self-funding things are slow.

    So over the next 5 or so years the data got stronger and stronger remember some of these experiments take 6 months to do and then repeat them compared to the 3 week quick fix EAE experiment. Then we too found out that immunology was not the solution to every thing and so had even more significance but was not the thing blinkered immunologists reviewers wanted to read more publication problems

    The paper bounced all over the place, nature (twice), science nature medicine, nature immunology, journal of clinical investigation, brain journal of experimental medicine twice journal of immunology 3 times etc and eventually you just have to get it out. Not in a big journal it makes less of a splash

    What was more galling was seeing the constant stream of tosh appearing in the above journals. Doing a few day experiment and showing a mechanism which now invariably resolves around T regs and Th17 that has little value to MSers.

    We had a mechanism but it was not dogma and establishment, and frankly does the mechanism matter if it works?

    As I have said before if you wrap dog pooh in a sexy mechanism it is still dog pooh but the reviewers of papers and grants lap it up. Leaves a bad taste in my mouth but then eating dog pooh should :-)

    Anyway that was therapeutic to me sorry for the rant. Onwards and upwards.







    ReplyDelete
  12. Ok. I think this is really important. We have what seems to be the potential for a cure for RRMS - at least if actioned before progression sets in. Or at the very least something that can reduce relapse rates to 0, without serious saftey issues. That is the most important thing I have heard in my decade of having MS. Yet the news is all about 3 x a week Copaxone insteaad of 7 x a week. It is ridiculous.

    How can we, the MS community, get behind this approach and support it to a conclusion? I think a concerted effort on behalf of us all, lead by Team G, could well see this come to fruition. How can we help? The MS community need to know that a cure could, for the first time ever, be in reach and is in danger of being largely ignored or sidelined or slowed down, because it is not part of Big Pharma's arsenal. That would be an absolute travesty.

    ReplyDelete
  13. What we need is a rich sugar daddy. Sadly I don't meet any.

    ReplyDelete
  14. I believe the guys doing the trials have convinced themselves that theirs is the best approach. We need to let these run to see where they lead.

    In USA there are places like the Howard Hughes foundation that says "you do good work-here's some cash- get on an do good work and stop wasting loads of time trying to get support..

    This is what the Wellcome Trust is aiming to do but the chance of dosh coming my way is not high. It is the Big Science that attracts the big money sadly in my opinion to the detriment of the rest of British Science who have even less avenues to follow innovative science. But it is their money and they can do with it as they like

    ReplyDelete
  15. That's just great. This is so bad. Can you imagine how many RRMSers will become SPMSers due to the fact that those that can refused to get behind a great idea that may have stopped us from becoming progressive? It's not fair. I'll be so angry is a discovery that made total sense in 2012 becomes the norm in 15 years time but won't benefit me because by then I have SPMS. We need an MS revolution.

    ReplyDelete
  16. What about Tovaxin/Tcelna...??

    ReplyDelete
  17. I simply don't accept we have to 'wait for a sugar daddy'. If there's a serious chance this approach is the beginning of the cure for MS then I think more can be done. The MS lobby is very powerful - potentially including the new first lady of the US (as well as an MP in the UK, a member of the H of L and a German Head of State). Equally, I know countless successful MSers - lawyers, businessmen etc. If there was a concerted effort to channel funding into this approach then I believe a difference can be made. It just needs someone to take up the challenge. MouseDoc - if you had more funding specifically for this approach, could you do more/work quicker?

    ReplyDelete
  18. What about Tovaxin/Tcelna...?

    Yes what about Tovaxin?. The company or its followers tried to sneak stuff onto the blog a few weeks ago, seemingly to advertise their press release, where they need funding for a trial.

    So is this question from someone with genuine interest or a company post again.?


    This is based on T cell vaccination done many years ago. I made a comment on this a few weeks ago

    ReplyDelete
  19. We do not currently get any funding for this work full stop, so with any funding we could do more work

    Prof Gs proof of concept study is funded by pharma for the blockade of neutralising antibodies.

    The beauty of the approach is that it has broad application to a number of T cell autoimmunities.

    There are some companies that aim to use antigen-specific therapies and some have trials ongoing. Some have in my opinion been misguided

    There is a thing called the immune tolerance network
    http://www.immunetolerance.org

    ReplyDelete
  20. "but we know it is an immune problem because relapses respond to immunomodulators."

    Most patients do not respond, however. The percentages of ARR reduction cited by DMDs are average values of selected and treatment unblinded patients (due to noticeable side-effects). Most individuals see no clear benefit.

    What you say is an oversimplification that distorts each patients own experience with MS and drugs. What is the problem with those who see no benefit from immunomodulators? They are the majority, you know.

    "The peptide fragments that cause the disease will be different for different individuals and this may change as disease evolves"

    Evolution in targets? Have you seen this in other diseases too??? You seem certain that peptide fragments cause the disease? On what proof?

    All in all, what the study just proves is that if you stop an immune response to something then there is no more immune response to it! Well done! Somebody forgot to prove that this immune response is causal to MS...

    ReplyDelete
  21. Most patients do not respond.

    Yes if you talk about interferons and GA, then the figures say 70% do not respond. In future unless I specifically say so please assume that DMT I am talking about are the new generation active agents. e.g Tysabri, gilenya and the new drugs round the corner.

    "Evolution in targets? You seem certain that peptide fragments cause the disease?"

    You know the immune theory, you know antigen selection if not read the education posts it has been done already and of course peptide fragments do not cause the disease. Using this paradigm it is the cells that recognise them. Stop being so paedantic you are twisting words.

    "All in All"
    You do phase II and III to test efficacy not phase I as in this study. This is safety.

    I have highlighted pros and cons and whether I think it could work and why it may not. One of those was there may be no autoimmunity.
    The only way to prove it is to treat it and it do something.

    Your comments add nothing except to say you are not interested in immune theory. We know that already. If you have something constructive to say....

    ReplyDelete
  22. Half of Tysabri, Gilenya treated patients still do not respond. Even stem cell treated patients remain stable for max 5 years. What else do you need to suspect that it is not the immune system to blame for MS?
    Ever thought about matching the unique facts about MS on the autoimmune theory? Dawson's fingers, for example. How do they form? Enlighten us please.

    ReplyDelete
  23. Think when people start getting stem cells early in disease..well no....you don't get it.

    The unique facts of MS...what are they? or are they VV facts you twist things all the time.

    Ever thought about matching facts about MS....... turn question around and CCSVI more very quickly runs into problems.

    When you first started to post I gave you the chance to have a soap box and tell us what you believe in your own words. You baulked just like you did when you brag about your blog. If the schelling tone is your bible then your must be able to distill it down into something consice and upto date and accomodate facts of MS which were just swept under the carpet when the facts do not help the cause.

    I have seen loads of infiltration lining up along blood vessels all over the CNS, it is not unique to Dawsons fingers in the brain.

    ReplyDelete
  24. Is this question from someone with genuine interest or a company post again?

    Again silence so I assume it was a company posting this.

    ReplyDelete
  25. "I have seen loads of infiltration lining up along blood vessels all over the CNS, it is not unique to Dawsons fingers in the brain."

    Dawson's fingers are unique in MS. Do you disagree?

    ReplyDelete
  26. "What we need is a rich sugar daddy. Sadly I don't meet any"

    You just need to work those murine charms a bit more, MD2. Am I right, MD?

    ReplyDelete
  27. Mouse Doctor - hire a health expert sales individual, and get him going. Put your funds towards his salary and let him find the wealthy people with MS. I guarantee there are a few multi millionaires with Multiple Sclerosis out there. Its simply a matter of finding them and soliciting their investment. This goes on all the time. If your theories are correct, they will stand up to the scrutiny of testing. So the focus shouldn't be on blog-debating with VV, but reading resumes of qualified health sales people who can solicit investors in the research.

    ReplyDelete
  28. Do you mean Sharon and Ozzy Osbourne for example they are worth a bob or too...But are they too tight?

    Almost got a Iron Maiden PhD studentship once...

    ReplyDelete
    Replies
    1. I suspect the Iron maiden tie-in ensures no money from the Osbourne's judging from the "These colours don't run episode".!

      Delete
  29. It is frustrating to see funding or politics keep good ideas from being investigated. Half-way to a cure to autoimmunity gets my attention.

    ReplyDelete
  30. Ann Romney has MS and had her husband been elected I would bet alot of funds would've been put towards research into curing auto-immune! You could still try contacting her to help fundraise for money!

    ReplyDelete
    Replies
    1. Michelle Obamas parents I believe has MS also

      Delete