Wednesday, 5 February 2014

Immunotherapy against EBV

Targeting EBV infected cells using immunotherapy. Is this the future of MS treatment? #MSBlog #MSResearch

"If you have been following this blog you will know that I am a firm believer that EBV causes MS. I say believer because when you apply Bradford-Hill's criteria for causation we are not quite there yet. We need experimental proof that EBV causes MS and we need to understand how EBV interacts with the human biology to trigger or drive MS. EBV also has the explain everything we know about the epidemiology of the disease; for example the worldwide distribution of the disease, sex ratio, month of birth effect, parent-of-origin effect, changing incidence of the disease, treatment response to various classes of drugs, etc."

"I say EBV trigger or EBV driver because we don't know if EBV acts early in the causal pathway as a hit and run agent that triggers MS and then MS runs amok without the need for an ongoing role of the virus. In comparison the driver hypothesis is that EBV drives the disease and is needed  throughout the course of the disease. If the latter is the case then we can target EBV with drugs or other anti-viral strategies to treat MS. This is what we are trying to achieve with the Charcot Project; the drugs we are choosing all target EBV or downstream events triggered by EBV."

"The case study below from Michael Pender's group supports an ongoing role for EBV in MS. They took CD8+ T cells from a SPMSer and supercharged them in the lab. These CD8+ T cells (a type of white blood cell) are akin to heat-seeking killer missiles that are targeted to EBV-infected cells within the body; they find these cells and kill them releasing proteins that literally punch holes in infected cells. The treatment was safe without any adverse events and remarkably the MSer improved. One swallow does not make a summer and this study will need to be repeated on a larger number of MSers. If this treatment is found to be safe it needs to be tested in a double-blind placebo-controlled study. I would suggest that instead of a placebo that an active control is used, for example CD8+ T cells directed at non-EBV viral proteins. The actve control is to make sure that the treatment response is not non-specific, i.e. simply due to something related to  the infusion of activated T-cells."

"Why is this research so important? Simply because it is challenging the current autoimmune dogma about MS that has a lot of holes in it. It is also part of the experimental evidence we need to prove that EBV is the cause of MS. Can you imagine what  this would do to the field of MS? What it will do to the treatment of MS? What it will do the market of MS DMTs? This could be the black swan moment I have been waiting for. In my mind it is not a question about whether a black swan will land, but when."

"For those of you confused by this talk of black swans should read my earlier posts on the subject."

Multiple Sclerosis Research: What does a black swan have to do ..., 06 Sep 2013; A good book to read about these improbable events is 'The Black Swan: The Impact of the Highly Improbable' by Nassim Taleb. The book focuses on the extreme impact of certain kinds of rare and unpredictable events ...

Who said a black swan has to look and feel like a feathered bird? 
"I would like to congratulate and thank Michael Pender and his colleagues for pursuing this work. You are brave people and your pioneering attitude and commitment to this field of work is much admired and appreciated. Please keep up the good work."

Pender et al. Epstein–Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis Mult Sclerosis Journal Epub

Defective control of Epstein–Barr virus (EBV) infection by cytotoxic CD8+ T cells might predispose to multiple sclerosis (MS) by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. We have treated a patient with secondary progressive MS with in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins. This adoptive immunotherapy had no adverse effects and the patient showed clinical improvement with reduced disease activity on magnetic resonance imaging and decreased intrathecal immunoglobulin production. This is the first report of the use of EBV-specific adoptive immunotherapy to treat MS or any other autoimmune disease.

46 comments:

  1. Brilliant work! Thank you for thinking and acting outside the box. Keep it up!

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  2. Bravo! Thank you Prof Pender.

    And thanks Prof G for a clear and understandable summary.

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  3. Remember black swans come from Australia:-)

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  4. Prof G,

    Any chance of you doign some joint work with Prof P (you could try and replicate his work and he could replicate your work (Charcot project))?

    If EBV is proved to be the trigger, I'm sure some of the current / in trial treatments will still be used (the antiCD20 drugs which target EBV infected B cells). Perhaps Prof Ps approach and the Charcot project approach will be other options for targeting EBV. Is the work by Prof P soemthign which only a pharma company could take forward or, if it does prove to be effective, can Prof P just allow other clinics to replicated the technique he / his team have developed?

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  5. If you so strongly believe in EBV why do you promote other drugs? Why do you never put your money where your mouth is? You always say something different every day- a flip flopper.

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    1. Re: "Why do you never put your money where your mouth is?"

      http://multiple-sclerosis-research.blogspot.co.uk/p/charcot-project.html

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    2. Re: "If you so strongly believe in EBV why do you promote other drugs?"

      Because I think they work via an anti-EBV mechanism; particularly the B-cell depleting drugs.

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    3. Re: "You always say something different every day- a flip flopper."

      I think I am pretty consistent; I haven't changed my treatment philosophy (T2T-NEDA) or my hypotheses about MS in the last 2 years. I having doubts about the contribution of epigenetics, but am waiting for more data. Still a NHS socialist at heart, but need to also realise that changes are afoot.

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    4. I'm happy to see that you Prof G keep an open mind on epigenetics (meaning that you doubt it).

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    5. Science is based on the concept of doubt, so flip flopping is better than dogma. I prefer doctors who can change their minds in the face of evidence.

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    6. Is dacaluzimab an anti EBV drug?

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    7. You haven't changed your hypothesis for two years??? Are you kidding me? That is not the comment from a true scientist. Alastair Compston has believed in campath and genetics for decades.

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    8. Re: "Is dacaluzimab an anti EBV drug?"

      Possibly; it boosts NK Cells that are antivrial. The truth is we don't know how it works.

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    9. Re: "You haven't changed your hypothesis for two years??? "

      Yes, but how does Campath work? Does it work by resetting the immune system or by depleting EBV infected B cells? Any ideas?

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    10. t true scientist looks at the facts and adapts their thinking.

      Thirty years ago suppressor CD8 T cells were the bees knees, then anergy then TH2 then T regs...a lot can change in a decade but then again there is a lot of dogma floating around

      Thirty years ago GA was a mimic of myelin basic protein now it is the "medical MS aspirin" :-)

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    11. The medical revolution from MS genetics has still yet to materialise.

      Thirty years ago we knew that there genetic effect of a protein and that there was an immune and genetic component in MS, today what is different? Where are the treatments that have come from this knowledge?

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    12. A belief is not a hypothesis. If you believe in something you believe in it, you can't change your mind. A hypothesis is a position you take and you test it and if the evidence does not support it you change your position. Hypotheses are for scientists and beliefs are for religious people or zealots. I am sure Prof. Compston is not a zealot; he is more likely to be a scientist and change his position depending on what the evidence shows.

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  6. Looks interesting and has two positives (i) doesn't involve pharma and (ii) doesn't involve EAE. The EAEologists have been the main reason why MS research has been so painfully slow. If EBV is the cause / trigger it was never going to be identified by the nerds who take great pleasure in putting to death tens of thousands of innocent little mice. No doubt Mouse will put up a defence, but as mice don't get EBV EAE was never going to deliver the goods.

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    1. So you throw down a guantlet or is that a bit of cheese.

      (i) Don't involve pharma..Is that a good thing I am still waiting to hear what approved procedures have come from non-pharma involvement.Will we expect answers in any real time frame. Great to see an n of 1.How long will it take to do n of 1000 and get the process approved.

      PS, I hope ProfP does it but lets see how long this process takes.

      Neuros have been leading bone marrow transplantation for years.
      How readily available is this?

      (ii) Does not involve EAE...Where did the idea of transferring CD8 T cells to get rid of viruses come from........Yep animals. Without those so call Nerds ProfP would not even know what a CD8 T cell is, let alone how to do something with them.

      P.S. I take great exception to the suggestion that researcher enjoy killing animals....they do not!

      Do you think that Neuros take great pleasure in not doing much to treat people with MS?

      Why have animal studies slowed down what gets done?...Neuros and pharma clearly will do studies that are not supported by EAE data.

      Mice don't get EBV I agree non human primates can have they given the answer?

      It has been clear as long as I have known EAE, that EAE is not MS and if humans think that, then that is problem of humans. Humans get EAE and that is not MS.

      I am not going to defend all EAEologists, Likewise i will not defend the actions of Neurologists

      As for delivering goods? That is what Tysabri seems to be doing

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  7. Please excuse my ignorance, how can we tell (without a blood test) if we have EBV? What are the symptoms?

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    1. Invariably no symptoms...the vast majority of humans are infected.

      Some people get glandular fever

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    2. I guess the next question is are there various strains of EBV that tend to cause different diseases/ levels of severity, like with HPV and only one leads to MS. This would explain why nearly everyone has EPV but only a few develop lymphomas / chronic fatigue / MS possibly.

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    3. This is complete BS. EBV does not cause MS. The only way EBV is involved with MS is that it evokes a inappropriate autoimmune response by genetically susceptible people. Anyone who proposes EBV is the direct cause of ms (meaning it causes damage to the CNS) is outside of the scientific community and goes against all of the MS research gathered through the years to date.

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    4. Re: "This is complete BS"

      They said this about an infectious cause of peptic ulcer disease as well, and cervical cancer, and rheumatic fever. Whenever there is a paradigm shift in a field the establishment who hides behind the current dogma rejects it. This phenomenon has been well studied and written about. If you are interest in the subject I suggest you read "The Structure of Scientific Revolutions" by Thomas S. Kuhn.

      http://en.wikipedia.org/wiki/The_Structure_of_Scientific_Revolutions

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    5. I sense the shadow of the black swan flying overhead. Prof Pender please keep up the good work.

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    6. To Anonymous 6/2/14 11:30am. Where is the evidence that EBV does not cause MS. Quote an effect that could not be achieved by a virus infecting cells in the immune system. If you cannot present such data then we must go looking for it. That is how science works. The exception proves the rule. It proves it wrong. Science is in the exceptions.

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    7. So why don't you have Michael Pender as a guest blogger and ask him straight up if the damage in MS is directly due to EBV? I would be interested in hearing his point of view.

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    8. "To Anonymous 6/2/14 11:30am. Where is the evidence that EBV does not cause MS."

      Since nearly all human adults are infected with EBV and only a small minority are afflicted with MS, logic dictates that EBV does not cause MS. Show me proof that it does. As the old saying goes, fantastic claims require fantastic evidence and there is not a shred that EBV is directly responsible for MS.

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    9. If you are EBV negative, the chances of you developing MS are near to zero. Is that enough of a shred for you?
      Just because EBV infection is very common in both MSers and the general population does not rule it out as being a causal factor of MS. Now if only there was a vaccine against EBV, the link should it exist could be proven beyond doubt.

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    10. "Just because EBV infection is very common in both MSers and the general population does not rule it out as being a causal factor of MS."

      There is no doubt in my mind that EBV is a factor in MS and if you could eradicate it you may not get MS in the first place. But to say EBV is the cause of MS is out if left field. It has no more validity than CCSVI. Keep thinking.

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    11. If you don't have EBV, you don't develop MS. It's not the whole story but it must make a strong contribution.

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    12. To: Anonymous Thursday, February 06, 2014 2:14:00 pm I developed Mixed Cellularity Hodgkin's Lymphoma that is caused by EPV. Not everyone who catches EPV gets MCHD, but it still causes it. The same is true of Burkitt's lymphoma.

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    13. Yes, EBV virus is involved in MS. I think most researchers agree here, but people with MS may have an inproper reaction to it compared to normal people. From your colleuges:

      http://www.news-medical.net/news/20120106/Study-shows-how-Epstein-Barr-virus-triggers-MS.aspx

      "Dr Meier and her team of collaborators found that, although the virus was not actively spreading, it was releasing a chemical message into areas of the brain nearby. This chemical message - made up of small RNA molecules - was activating the body's immune system, causing inflammation. This damages nerve cells in the brain and causes MS symptoms."

      Note that Dr. G is mentioned in this article, but I can imagine that the vast majority of researchers do not believe that EVB is the direct driver of MS. Regardless of whos right or wrong, eliminating EBV permanantly from humans could prevent MS.

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    14. Smoking causes lung cancer. Not all smokers get lung cancer. The fact that not all smoker get lung cancers does not mean that smoking does not cause lung cancer.

      EBV causes MS. Not all people infected with EBV get MS. The fact that not all people infected with EBV get MS does not mean EBV does not cause MS.

      The best protection against not getting MS is not getting EBV. This suggests EBV is the cause of MS.

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    15. To Anonymous 6/2/14 11:30am, the tone of your comment is not conducive to clear thinking; You need to lay out your arguments in a clear, concise and logical manner. Simply, stating the dogma is not going to convince anyone. Why don't you think EBV does not cause MS? Why do you think it is BS?

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    16. What if..smoking causes some lung cancers. Some smokers develop lung cancer. Not all lung cancers are caused by smoking. Smoking is a contributing factor. EBV causes some MS. Some with EBV develop MS. Not all MS is caused by EBV. Therefore, EBV + is contributing. But statistics have shown that MSers are 99.9% EBV +. But if EBV was not causative then there should be cases that are EBV-. There are cases of lung cancer without smoking.

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    17. "Smoking causes lung cancer. Not all smokers get lung cancer. The fact that not all smoker get lung cancers does not mean that smoking does not cause lung cancer."

      Here's the difference: smoking cigarettes significantly increases your risk of getting lung cancer. Having EBV does not increase your risk of getting MS. Bad analogy.

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    18. Anonymous Thursday, February 06, 2014 11:03:00 pm But not having EPV does significantly reduce your risk of MS so it is not a bad analogy. The opposite has not been measured because most people have it.

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  8. Great! Especially since this supports the idea of an ongoing role for EBV.
    Scientists & doctors are good at finding cures for infectious diseases, so any evidence that MS is an infectious disease makes me very happy.

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  9. Help me understand this. The paper says: "We have treated a patient with secondary progressive MS with in vitro-expanded autologous EBV-specific CD8+ T cells directed against viral latent proteins."

    Does that say to you that if this is replicated we can look forward to MS being treated with a lab procedure in the future? Or simply that pharma is likely to develop drugs that will work via a similar mechanism?

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  10. Even though this is a research on another patient community ME, it is interesting concerning in their comment on EBV: "As EBV is known to be controlled by cell-mediated immunity, a diminished memory T- and B-cell response may result in impaired control of EBV. EBV replication is risk factor for development of lymphomas and autoimmune diseases both occurring at enhanced frequencies in CFS patients." This current research may factor in other diseases where EBV could be considered a relevant trigger in other disease groups.

    http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085387
    Deficient EBV-Specific B- and T-Cell Response in Patients with Chronic Fatigue Syndrome

    Madlen Loebel equal contributor *, Kristin Strohschein equal contributor, Carolin Giannini, Uwe Koelsch, Sandra Bauer, Cornelia Doebis, Sybill Thomas, Nadine Unterwalder, Volker von Baehr, Petra Reinke, Michael Knops, Leif G. Hanitsch, Christian Meisel, Hans-Dieter Volk, Carmen Scheibenbogen

    Published: January 15, 2014
    DOI: 10.1371/journal.pone.0085387

    Abstract

    Epstein-Barr virus (EBV) has long been discussed as a possible cause or trigger of Chronic Fatigue Syndrome (CFS).

    In a subset of patients the disease starts with infectious mononucleosis and both enhanced anddiminished EBV-specific antibody titers have been reported.

    In this study, we comprehensively analyzed the EBV-specific memory B- and T-cell response in patients with CFS. While we observed no difference in viral capsid antigen (VCA)-IgG antibodies, EBV nuclear antigen (EBNA)-IgG titers were low or absent in 10% of CFS patients.

    Remarkably, when analyzing the EBV-specific memory B-cell reservoir in vitro a diminished or absent number of EBNA-1- and VCA-antibody secreting cells was found in up to 76% of patients.

    Moreover, the ex vivo EBV-induced secretion of TNF-α and IFN-γ was significantly lower in patients. Multicolor flow cytometry revealed that the frequencies of EBNA-1-specific triple TNF-α/IFN-γ/IL-2 producing CD4+ and CD8+T-cell subsets were significantly diminished whereas no difference could be detected for HCMV-specific T-cell responses.

    When comparing EBV load in blood immune cells, we found more frequently EBER-DNA but not BZLF-1 RNA in CFS patients compared to healthy controls suggesting more frequent latent replication.

    Taken together, our findings give evidence for a deficient EBV-specific B- and T-cell memory response inCFS patients and suggest an impaired ability to control early steps of EBV reactivation.

    In addition the diminished EBV response might be suitable to develop diagnostic marker in CFS.

    Interesting comment on EBV & ME:
    http://cfspatientadvocate.blogspot.nl/2014/01/dr-carmen-scheibenbogen-berlin-charite.html

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  11. Prof G,

    Doesn't it seem odd that the treated patient was said to have SPMS, but was still showing Gd-enhancing lesions?

    And the authors measured a decrease in intrathecal IgG production - have others used this as a measure of disease activity (or decrease in activity)?

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  12. "If you don't have EBV, you don't develop MS" is not exactly true.

    Children do get MS without EBV

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  13. AnonymousThursday, February 06, 2014 7:27:00 pm "Children do get MS without EBV" Can I have a reference please.

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    1. This post from Prof G has a reference:
      http://multiple-sclerosis-research.blogspot.com/2013/09/ebv-in-childhood-ms.html

      He says "You will note that not all childhood-onset MSers are positive for EBV, which is a strong argument against the virus causing the disease. I agree that this is one hole in our EBV theory. ... "

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  14. Prof. G..I will tell you that I am excited for the research on EBV that you're doing. Honestly my first relapse, which I didn't know at the time was MS and not diagnosed until last month, was a feeling of complete and utter fatigue and I thought at the time that I felt like had Mono! I ended up sleeping literally for 4 days. Other symptoms that manifested themselves were an inability to pee and I had to have a catheter put it. MRI done on my spine (ha) no kidney, bladder, UT infection, no one could explain it. I just thought I had some kind of weird virus. 8 months later my outer ear canals started itching in both ears with no known cause (and still itch today). Then I fell down a flight of stairs a year ago February and woke up numb from the waist down two weeks later. Another MRI confirmed a bulging disk impinging my nerve on the left side, but it didn't explain the symptoms on both sides. Eventually the numbness receded and now I am only numb in my feet and ankles with numbness moving around up and down to my knees on bad days. I do think this has something to do with EBV and I hope something comes out of this!

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