Wednesday, 20 January 2016

CrowdSpeak & ResearchSpeak: EBV and HSCT

Could HSCT be working via EBV?  #MSResearch #MSBlog #CrowdSpeak #CrowdacureMS

"Yesterday the Mouse Doctor asked me how do we reconcile the results of bone marrow transplantation (BMT) and/or HSCT with the EBV hypothesis of MS? The simple answer is I don't know. However, all high-efficacy DMTs have effects on B-cells including BMT/HSCT. This form of therapy may therefore be working via depleting B cells; not too dissimilar to what occurs with cladribine, alemtuzumab, mitoxantrone, cyclophosphamide and anti-CD20 therapy (rituximab, ocrelizumab, ofatumumab)."

"The case studies below show that BMT can actually eliminate EBV from the body or at least a strain of EBV. I am aware of a similar unpublished case with MS who was found to be EBV negative 5 years after having received alemtuzumab treatment for very active MS. This is why the very promising results of BMT/HSCT trials are not incompatible with the EBV causation hypothesis. What I can say is that until we do the trial of targeting EBV with a specific anti-EBV drug we won't be able to sort out this issue. Can you imagine what would happen to the field of MS if a small molecule anti-EBV drug proved to as effective as HSCT? That is what I refer to as a black swan.This is another reason for us to get our Charcot 2 project off the ground as soon as possible. Our fund raising is going very well with close to 200 donors already. For those of you who have donated already, thank you it is much appreciated. Despite early reservations I am now thrilled to have launched this initiative; it is taking PPI to another level at least in the UK. Once we have reached our target we plan to get the lab work completed as soon as possible. We will also display the results to you in real time and engage you with the design of the next study and the associated grant application. This is what we call citizen-informed science."

Click here to find out more!


Background: Wild-type strains of Epstein-Barr virus (EBV) can be distinguished on the basis of variations in the molecular weight of virus-encoded, growth transformation-associated proteins. 

Case studies: This approach was used to study the persistence of EBV in two seropositive recipients of allogeneic bone marrow transplants. The first patient received marrow from her EBV-seronegative brother, became EBV seronegative after grafting, and remained so for greater than 1200 days. Subsequently, she became infected with a new EBV strain that differed from her pretransplant strain but was indistinguishable from the virus isolated from her husband. The second patient received marrow from his EBV-seropositive brother. This patient showed only a transient decrease in IgG antibodies to EBV capsid antigen. His pretransplant strain differed from the virus of his donor. On days 252 and 915 after transplantation, lymphoblastoid cell lines were grown from the peripheral blood of the patient and were found to carry exclusively the virus of the donor. 

Conclusions: These results suggest that the latently EBV-infected host cells reside in a cellular compartment that can be destroyed by graft-versus-host reactivity, irradiation, or cytotoxic drugs. Hemopoietic tissue is the most likely candidate.

CoI: Team G will be recipients of a grant from Crowdacure to perform this research

22 comments:

  1. I see no incompatibility between the (BMT) and/or HSCT and the EBV hypothesis of MS. EBV leads to the formation of damaged B cells, just like it does in mixed cellularity Hodgkin's lymphoma. The treatment kills those cells, destroying the cancer or the cause of MS. The specific damage to the B cells required to cause MS or cancer probably occurs very infrequently and so the risk of relapse is moderately low. The cancer cells in mixed cell Hodgkin's make up only a tiny part of the lymphoma, most of it is other cells, whose behaviour is disrupted by the cancer cells, are non cancer immune cells. The actual cancer cells do seem to express signs of EBV activity.

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    1. Hodgkin's lymphoma also causes immune responses, rashes and itching, long before the lymphoma is big enough to be found and in parts of the body no where near the site of the cancer (say the cancer being in the neck and the rash on the legs). Imagine a similar set of mutated B cells either dividing slowly or not at all then they could cause immune responses, like in MS, but be almost impossible to spot.

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  2. We need a breakdown of why you guys found Monday's Panorama too be, as MouseDoc said, utter "fluff".

    The neurology clinics of every NHS hospital were swamped with calls from desperate MSers demanding HSCT immediately. It may have set a seriously dangerous precedent. Are you ready for it?

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    1. Re: "We need a breakdown of why you guys found Monday's Panorama too be, as MouseDoc said, utter "fluff"."

      I am preparing a response and will post it in the next few days. Not necessarily fluff but not an a fair representation of the state of play of both HSCT and what is out there already for pwMS.

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    2. The programme was information light as Matt who I believe has been on the Journey himself said "disappointing"

      The programme could have told us what was really involved and to explain the biology and the treatment regime rather than just show a liquid nitrogen tank, it could talk about the risk benefit process and why did one person say they would rather have fight with Mike Tyson.

      Lets face it is the ultimate immunosuppression (the non myeoablative) shy of completely destroying the bone marrow the treatments may involve rituximab, cyclophosphamide, anti-thymocyte, Alemtuzumab, clofarabine, it could have been BEAM (although it wasn't) we were not really told what was being used, so how to assess risk. All we saw was people doing well so I am not surprised that the NHS is being deluged with calls.

      Foreseeing the information one could ask what is the capacity of the NHS to deal with the deluge of calls. Maybe there is a lot of spare capacity so maybe we could push this through and get the answer. If there was proper follow-up I actually believe that it could be done, but would the trusts pay for it as it has not been NICEd because if a neuro wants it done there is nothing to stop them trying, if the trusts pay for it. This off label issue could have been adressed.

      What is the evidence that it really is better than alemtuzumab (excluding the autoimmunity risk). In the phase II trials where people were very active like the HSCT recipients the data was very good. I wonder if Prof Coles could have made the same video with some of his patients

      Please do not take this to say that I do not believe that HSCT can work, it clearly can. It would work best for the people who are newly diagnosed as they have accumulated least damage. However at the moment it is being offered to people who have failed everything.

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    3. If I may suggest: a comparative table of induction therapies is long due.

      Some RRMSers are doing well on current high efficacy DMDs but are nearing their 10 year birthday since onset.

      My understanding is that the HSCT efficacy window is about 10 years. As such, even good responders on current DMDs are now pondering whether to sit tight or jump ship before its too late...

      After all, this blog's mantra has always been "treat early and aggressively (but safely)". Should the treatment algorithms be revisited at this stage in light of the 10yrs window mentioned above?

      Tony F

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    4. What is the evidence that it really is better than alemtuzumab MouseDoctorWednesday, January 20, 2016 12:37:00 pm(excluding the autoimmunity risk). In the phase II trials where people were very active like the HSCT recipients the data was very good. I wonder if Prof Coles could have made the same video with some of his patients

      I have not watched the program so I'm speaking out of my ass. My partner chose HSCT over Lemtrada because of the auto immune issues which are rife in her family. What is the evidence that she can't have Lemtrada when HSCT stops working, unless by then she goes into a fully progressive phase? As I said, I haven't watched the program in question but I do have to say she is doing far better after HSCT then she was on Tysabri or even this time last year. She has no balance issues for now, no pins and needles and some other small things. I know I know I should google youtube on CCSVI who also claim to be feeling great. My partner made a choice to have HSCT not because of whether it's better or not than Lemtrada, but because she liked the HSCT risk profile better than Lemtrada's. If she needs Lemtrada in the future she will deal with it then. Or they may even figure out how to lessen the secondary autoimmunity associated with Lemtrada. My partner had to travel overseas for the procedure because she is 40, was a year from diagnosis and not severely disabled. Had she waited for the option in Australia things may have been drastically different. Choice and accurate information are the only things that can help MSers make decisions in a capitalist world with free travel, while scientists debate and create algorythms on risk and safety profiles based on general statistics. 4 neurologists advised her against the procedure and one said (honestly at least) she doesn't know what she would do in my partner's position. We are thrilled with the choice we made, prepared to take the future as it comes and frustrated as hell for the most difficult year of our life trying to obtain accurate information on HSCT. I'm a non medical professional who has now read 46 articles and studies on HSCT because the medical profession would not give me information which is actually available but has to be mined. I would be thrilled if a neuro consulted my practice with a legal problem and I offered him or her to a short term solution or the option to go home study all the law on the issue then arrange his own defence in Court.

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  3. What would you prefer; a large number of small donors or one big angel donor?

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    1. Re: "What would you prefer; a large number of small donors or one big angel donor?"

      Both! In terms of the aims of this project in getting the crowd to support it I would prefer 10,000 £1 donations. It would be simply amazing to get as many supporters behind this project as possible. Crowdfunding is about microfinance. However, getting one large donation would be great in that it speeds up the research process.

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    2. I note some £1 donations are coming in. This is good news. Thank you.

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    3. prof a few students want to donate 50p or so each- this is not possible?

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    4. Re: "prof a few students want to donate 50p or so each- this is not possible?"

      I will contact Crowdacure; apologies, but this is out of my control.

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    5. Hi Gavin,

      The minimum donation with a card is 30p so they should be fine. However, as Stripe has a fixed fee of 20p per payment I would suggest bundling the donations into a bigger one if possible.

      Best Regards,
      CTO
      Crowdacure Ltd

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  4. This is fascinating and compelling. I'll be making a £1 donation to Charcot for sure! And I've asked family members if they'd like to do the same.

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  5. Just wondering... In the meantime, is there anything a person with MS can do to limit their EBV activity? Apart from maintaining general health. Eat lots of garlic or something? Sorry, I know, nutriceuticals...

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  6. Is this of interest

    Drug shows promise for halting cancer virus
    http://www.medicalnewstoday.com/articles/305315.php

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    1. Rapamycin is an immunosuppressant. And this is what I see the positive results including the HSTC: for me is the strong immunosuppression responsible for the positive results, because if EBV infects B lymphocytes strong immunosuppression eliminate the virus or part (perhaps even remain in the lymph nodes or thymus ) ... and this gives even object to another study: if EBV lever MS, individuals who went through the transplant was re-infected by EBV as this new immune system would behave? MS return?

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    2. They seem, from the press release, to see direct suppression of the virus infected cells, forcing them to become suspended, on top of a killing of cells.

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  7. Is there someway of testing the EBV status of people undergoing alemetuzumab (or HSCT)before and after treatment. Is there a difference between the EBV status of those in apparent 'remission' and in those with reactivation of their disease?

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  8. I was thinking about this post last night. As a comp eng I know the value in rebooting things. It makes sense that if the immune system is rebooted then as we say 'it comes up clean' and we know that folks lose tetanus immunity after these processes.

    Given that we know that anti cd20 deplete the B cells and we're not sure if EBV infected B cells are preferentially targeted is it possible that all B cells are uniformly targeted and that EBV is kept below some magic number. Is it possible that once EBV gets above a certain point that it triggers something, this pattern would fit with a relapse pattern.

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  9. One more thought; do we know if a relapse is a stochastic process? Is it that anti cd20 reduces the number of B cells and that shifts the relapse rate 2 or so std deviations from the mean?

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