Black Swan

Most of you know by now that I am one of the main proponents supporting EBV as the primary cause of MS. I think EBV is actively driving MS disease activity. The corollary to this statement is that we may be able to treat MS with anti-EBV drugs. We have suggested that all MS DMTs work by affecting memory B-cell biology and that this is the cell that host the EB virus. At Barts-MS, we have an active research programme to test anti-EBV drugs in MS.

One way of targeting EBV is via immunotherapy and Michael Pender, from Brisbane, has been promoting this strategy for over a decade. His data on using autologous ant-EBV CTLs (cytotoxic T-lymphocytes) is impressive. Almost too good to be true! Most of the MS community has dismissed his data as being biased due to being unblinded and from one centre. However, if you drill down into his data you will see that most of the MSers he has treated have had quite advanced disease with high EDSS scores and the improvements in disability have been so profound that it would be difficult to ascribe this to biased EDSS-rating. I am convinced that Michael Pender is onto something big and something very important.

This is why the ATARA Bio early phase 1b data is my one of my #ECTRIMS2019 highlights. Instead, of autologous cells, ATARA Bio is using MHC-matched allogenic CTLs. The good news from their poster presentation is that these cells seem safe as a treatment and at the high doses they are reproducing Pender’s single-centre results.

I agree it is too early to be jumping up and down and that we need to wait for the results of a randomised double-blind controlled study, but imagine a world in which we treat MS with anti-EBV CTLs and our MSers notice profound improvements in disability? This would be a true paradigm shift, a black swan event! Overnight MS would be classified as an infectious disease. Could you imagine what would happen to the MS DMT market? I sincerely hope for the MS community that this remarkable story pans out to be true.

Prof G’s ECTRIMS Highlight #2

Pender et al. Preliminary safety and efficacy of ATA188, a pre-manufactured, unrelated donor (off-the-shelf, allogeneic) Epstein-Barr virus-targeted T-cell immunotherapy for patients with progressive forms of multiple sclerosis. ECTRIMS 2019 Abstract: P1657.

Introduction: Evidence suggests Epstein-Barr virus (EBV) infection is associated with multiple sclerosis pathogenesis. In patients (pt) with progressive forms of MS (pMS), autologous EBV-specific T cells may prevent progression and improve symptoms (Pender, et al. JCI Insight. 2018).

Objectives: To evaluate ATA188, an off-the-shelf, allogeneic, EBV-targeted T cell immunotherapy comprised of HLA-matched, in vitro-expanded, cytotoxic T lymphocytes in a first-in-human, multicenter, 2-part study in adults with pMS (NCT03283826). Preliminary data are reported.

Methods: Eligible pt (age 18‒< 66) are EBV-seropositive with pMS and an Expanded Disability Status Scale (EDSS) score of 3‒7. Cohorts (cht) 1‒4 (6‒9 pt/cht) receive escalating doses of ATA188. 1° endpoints: safety and identification of the recommended phase 2 dose (RP2D) of ATA188. Efficacy criteria: EDSS, MS Impact Scale-29, Fatigue Severity Scale, and 12-Item MS Walking Scale scores; timed 25-foot walk; 9-hole Peg Test; and visual acuity. A responder (R) has sustained ≥ minimal clinically significant (MCS) improvement from BL in 2 consecutive evaluations on ≥2 efficacy criteria; a partial responder (PR) has ≥ MCS improvement from baseline (BL) in any 1 evaluation on ≥2 efficacy criteria; and a non-responder (NR) has ≥ MCS decline from BL in any 1 evaluation on ≥2 efficacy criteria (if both criteria are met, pt is NR). Plasma inflammatory biomarkers (IL-2, IL-1β, TNF-α, IL-6) are monitored throughout treatment.

Results: As of 27 May 2019, 19 pt (53% male; median age, 56 years) have enrolled (6 in each of cht 1‒3; 1 in cht 4) and received ≥1 dose of ATA188. Treatment-emergent AEs (TEAE) occurred in 63% (12/19) pt and treatment-related AEs (TRAE) in 37% (7/19) pt; 1 pt (cht 2) had a grade ≥ 3 TEAE, and 1 (cht 4) had a serious TRAE. No dose-limiting toxicities or fatal TEAE have been reported. Efficacy data are available for cht 1 and 2: cht 1, 1 R, 1 PR, and 4 NR at 6 months and 1 R, 0 PR, and 1 NR at 12 months; cht 2, 2 R, 4 PR, and 0 NR at 6 months. On measures of disability, 3/6 showed improvement and 3/6 showed decline in cht 1; 4/6 showed improvement and 1/6 showed decline in cht 2. Inflammatory cytokines remained at or near baseline.

Conclusion: Preliminary data indicate ATA188 is well tolerated and improves efficacy measures in adults with pMS, even at lower doses. These results support continuing part 1 to identify RP2D for part 2, (randomized, double-blind, placebo-controlled portion).

Pender et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight. 2018 Nov 15;3(22). pii: 124714. doi: 10.1172/jci.insight.124714.

BACKGROUND: Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy.

METHODS: An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro-expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. Following adoptive immunotherapy, we monitored the patients for safety and clinical responses.

RESULTS: Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher’s exact test).

CONCLUSION: EBV-specific adoptive T cell therapy was well tolerated. Clinical improvement following treatment was associated with the potency of EBV-specific reactivity of the administered T cells. Further clinical trials are warranted to determine the efficacy of EBV-specific T cell therapy in MS.

TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000422527.

FUNDING: MS Queensland, MS Research Australia, Perpetual Trustee Company Ltd., and donations from private individuals who wish to remain anonymous.

CoI: multiple

77 thoughts on “Black Swan”

    1. Relapses and MRI activity are not the disease we call MS; they are in response to what is causing the disease so don’t be surprised if they don’t correlate with efficacy.

  1. Thanks Prof G. I’m going to get straight to the point. There must be a drug out there we can take to replicate these results. If so what drug? Please do not sit on the fence. Tell it like it is.

      1. Professor, does that really mean there is nothing we can ask a doctor for privately (not on NHS, maybe even not in the UK) to prevent EBV from causing damage?
        Best wishes,

      2. Yes, that is correct. But please remember all of the licensed DMTs target memory B-cells and hence may work against EBV.

  2. We’ve been through this black swan talk before. It does no good to patients eagerly awaiting a breakthrough only to have the rug pulled out. Borderline cruel.

  3. JK Rowling donated £15 million to the MS research centre in Edinburgh named after her mother who died of MS in her forties.
    Is that research centre looking at Epstein Barr virus?
    If not, why not?

    BTW £15 million for research is pointless imo.

    The people who have MS NOW are expected to wait for decades for the cure for this brain shredder, watching money like that being thrown at it, when in reality 10 times that amount has probably been put into MS research the world over for DECADES already, and what has it achieved?

    Diddly squat!! Nada
    They still don’t even know what causes it for god’s sake!!!!!

    Can’t the NEUROLIGISTS partner up with HAEMOTOLOGISTS and work together regarding Epsten Barr Virus?

    1. “Is that centre looking at”….It is a largely a hard core remyelination centre, much of it is basic science.

      We could do have done a lot with £15 million…we would not have had a cost effective treatment for all for example.

      1. Sorry,,,but for me with a shredded brain, I find that post hard to decipher.
        Big pharma have no interest what so ever in curing MS.
        Why would they? They make billions a year out of people who are having their brains shredded day by day by MS which Epstein Barr virus likely kicked off….
        As for all this claptrap of blind and double blind trials and more and more waiting…us lucky souls get to go blind in real life through MS.
        Michael Pender must be SICK of trying to get people to listen for more than TEN YEARS.

      2. Maybe I am misunderstanding your comment but how can there be a cost-effective treatment for all when all are not treated equally?
        Remyelination sounds good to me

    2. Yes, we are collaborating with oncologists on EBV. We need to. Why reinvent the wheel? They have the expertise and knowledge in relation to EBV that we need to apply to MS.

      1. So what do we say to our neurologists scattered across the country?

        Can we demand certain treatment or is that not allowed?

        I think my neuro may be one of the ones who listens (though admittedly I’ve never went up against him yet!) and he was suprised I knew about you and said your name before I could get it out.

        Are we able to demand to see an oncologist as opposed to neuros do you know?

  4. The links to EBV have always been there for me. I remember my views being dismissed by my consultant when I was diagnosed and asked about a possible link. Im glad there is some growing momentum here and we can see some targeted treatment hopefully. I think the fact some people feel better on specific diets makes sense to (ie links to the “feeding” of EBV are there too but id rather kick it out the park rather than suppress it)
    Any particular reason the trial was done on more progressed MS, I think surely the earlier the better? Is there any appetite to go down this route? In terms of the effect on the DMT market, well it would be basically be a cure and pharma surely wont like that (i know i sound rather tin foil/cynical here but can understand the £££ influence here)

  5. News like this gives me such hope! Even if too late for me, to hear words like ‘improvement ‘ and know there is hope for the near future is wonderful.

  6. This is the sort of post I love!

    Pender’s results are remarkable. But what are the possibilities of antivirals, would that not be the best option for lowering side effect risk? Research goes on in this area doesn’t it… 🙂

  7. Look at the big picture. Look at the sum of the evidence: multiple sclerosis is caused by canine distemper virus.

      1. Yes. It has been shown that MS patients have elevated antibody titers to canine distemper virus….. and it is not just a matter of immune system dysfunction resulting in high levels of antibodies to everything, because these same MS patients do not have elevated levels of antibodies to other viruses.

        There was a report in the 1970s of 3 young sisters who developed MS. Their dog was sick with canine distemper virus some time before they were diagnosed. A fourth sister did not develop MS. She moved out of the house before the dog became sick.

      2. Any possible link between canine dystemper virus and MS has been comprehensively debunked.

      3. You’re welcome 🙂

        The role of canine distemper virus (CDV) in human disease

        CDV has been postulated to play a role in MS primarily on the basis of epidemiological evidence that has, as yet, not been confirmed. Thus, it is hypothesized that the geographical distribution in incidence is due to the stability of CDV, which would decrease towards the equator 165. An MS link was also promulgated as a result of the so‐called MS ‘outbreak’ that followed the invasion of the Faroe Islands by British troops during the Second World War. It was hypothesized that infected dogs brought CDV to the Islands and that this was responsible for the ensuing MS ‘outbreak’. However, evidence for the existence an ‘outbreak’, and for the diagnosis of canine distemper, has been questioned. The evidence for the ability of CDV to cause systemic infection in human beings is also very weak. Morbilliviruses are readily cross‐neutralized and this has been exploited in the past in using measles vaccine to protect cattle from rinderpest when no appropriate vaccine was available. Hence the fact that most of the human population would have been exposed to MV at an early age and probably would have carried a maternal antibody against MV that could also neutralize CDV would hinder or prohibit infection by CDV. Cook et al 166 suggested a link to CDV but this has not been confirmed. Their studies were confounded by the cross‐reactivity of CDV with MV‐specific antibodies and the general non‐specifically elevated levels of viral antibodies found in MS patients. Recently, brain samples from patients with MS were examined by immunocytochemistry (ICC) using MV and CDV monoclonal antibodies 167. All sections were negative except for one antibody, which bound to 8/9 MS plaques and 2/5 herpes simplex virus encephalitis brain samples, but not six controls or four patients with ischaemic stroke. However, no evidence for the presence of MV in MS plaques was obtained by RT/PCR, calling into question the specificity of the antibody. The authors suggested that the monoclonal antibody may recognize an epitope on an as yet unrecognized morbillivirus present in the human CNS that might be implicated in MS pathogenesis or represent a protein that is up‐regulated during inflammation. The latter is most likely the correct interpretation, as Sheshberadaran and Norrby identified a cross‐reacting epitope on a 79 kD stress protein 168.

        CDV has also been proposed to play a role in PD based on epidemiological evidence of higher than expected dog ownership in the North of England amongst patients, compared with age‐ and sex‐matched controls 169. Other studies were not able to confirm these observations 170. Nevertheless, it led to a number of studies looking for CDV in Pagetic bone tissues. RT/PCR on RNA samples extracted from decalcified bone indicated that CDV was present in 8 of 13 samples but MV was not detected. When the amplicons were sequenced, they were identical to the Onderstepoort strain and not to wild‐type strains of CDV. The significance of these results is not clear and contamination cannot be ruled out. Several other studies have not been able to confirm the presence of CDV‐specific RNA in nucleic acids extracted from bone, but of course in science it is formally impossible to prove the absence of anything 152, 154. ISH studies using CDV‐specific probes were carried out 171. The data appear consistent but the specificity was not high and only 41% of the PD samples were positive with probes for the N and F mRNAs of CDV, even though probes for all genes and anti‐ and genomic RNA were used. The latter may be explained by the much higher copy numbers of mRNA than genomic RNA present in infected cells. Alternatively, it may be a technical defect in the study, as the authors were similarly unable to detect genomic RNA in dogs with metaphyseal osteopathy, whereas mRNA probes showed positive results. Signals were observed not only in osteoclasts, but also in osteocytes and osteoblasts, whereas the paracrystalline arrays (see above) were observed only in osteoclasts. Recently, Hoyland et al compared in situ RT/PCR, ISH, and RT/PCR for CDV detection in Paget’s disease 172. Only in situ RT/PCR was positive in all ten bone samples and not in controls. As commented on above, it is notoriously difficult to obtain specific responses using this technique and hence it must be concluded that the link between CDV and PD is far from established.

      4. In addition, in the UK, canine dystemper is very rare due to the widespread uptake of vaccination against the virus.

      5. You still didn’t address finding of elevated antibodies to distemper and not measles or other viruses in the above referenced paper. What is the flaw in the methodology in that paper? You cannot answer that question, can you?
        You are trying to fit round peg in square hole with EBV. It is not related to MS.

      6. The paper elegantly spells out why this is not “cross reactivity.” If it is cross reactivity, then why are distemper virus antibodies elevated relative to measles? You appear not to understand the science.

      7. There have been so many pathogens cited as the cause of MS that I’ve lost count (e.g. Chlamydophila pneumoniae). Almost all have been ruled out due to the epidemiological data and lack of supporting controlled trials. I have no doubt that MS is caused by a virus or bacteria (EBV is extremely compelling). With the new technologies available to detect pathogens / antigens, this is where the research focus should be. The problem is how to detect these in what is effectively a compartmentalised disease. We then need drugs that cross the BBB.

        With that said, I applaud the Bart’s team for thinking outside the current dogma that MS is simply an autoimmune disorder.

      8. Sorry too many nots there. If we reduce the amount of distemper in dogs by vaccinating we should see a drop in MS. Did we?

      9. Spot on! I successful vaccination campaign to reduce distemper should prevent MS; it didn’t.

      10. I remember when aluminium caused Alzheimer’s, ever one was convinced until someone pointed out the aluminium in the stain they were using to identify the plaques. Science moves on. The “exception proves the rule” and it proves it is wrong.

      11. Nick: Epstein Barr virus gave me Hodkin’s Lymphoma. I does not do it to everyone even though 95% of the population has EBV. That everyone has something does not mean the outcome is the same for everyone. See measles, all my uncles and aunts caught measles before vaccination occurred. It only left one of them deaf. Can you reference the papers showing the reduction in MS with distemper vaccination please.

      12. Actually epidemiological studies have been mixed with multiple published studies revealing correlation between distemper and MS (including reduced rates of MS after dog vaccinations became routine). Some other epidemiological studies have been negative in this regard.

        But it is difficult to determine, because up to 50% of cases of distemper in dogs are sub-clinical, and many dogs go too long between vaccinations, so simply instituting a “vaccination program” doesn’t reliably tell one whether or by how much distemper infection rates are truly falling.

        Also keep in mind that distemper in dogs causes CNS disease very similar to MS in humans. EBV is ubiquitous…. almost everyone has it.

        EBV as a cause of MS is a perfect example of scientific group-think. An idea becomes fashionable and organizations like MS Society embrace it. Result is an echo chamber. Look at the evidence. Think for yourself.

  8. Professor, does that really mean there is nothing we can ask a doctor for privately (not on NHS, maybe even not in the UK) to prevent EBV from causing damage?

    Best wishes,

    1. Nick
      If canine distemper virus was a cause of MS, you would expect populations such as the Inuit and Sami peoples to have a high incidence as they live and work in close proximity to large canine populations for sledging etc.
      Yet MS is almost unknown in these populations.
      Also the work you cite is very old, it hasn’t been widely replicated, which you would guarantee to be the case if it was correct.

      1. From the paper you cite,

        While some have suggested a link between Canine Distemper Virus (CDV) infections and MS (Clemmons, 1992, Lincoln et al., 2008, Simon et al., 2010), this remains largely unconfirmed. Additionally, the common practice to vaccinate dogs against CVD combined with no apparent decrease in MS incidence has further diminished this concern.

        In addition, how do you explain the increased risk of MS with latitude? More dogs the further North/South you live?
        I think not.

      2. 1. I agree that the authors of the study from 2019 – showing a link between multiple sclerosis and dog exposure in the years prior to diagnosis – do not believe that distemper causes MS. But that does not change the fact that their study supports the theory that canine distemper does cause MS.

        2. Regarding your second point, the latitude question fits perfectly with the canine distemper hypothesis. Thank you!

        “”Though distemper occurs worldwide, the virus is readily inactivated by warm temperatures, which would fit with the low incidence of MS in subtropical and tropical areas. Furthermore, Dr. Cook said, in hot climates people are less likely to keep their dogs in the house, and without intimate contact, the dog virus may not spread easily to people.”

      3. 1. Regarding your first point: I agree that the authors of the study – which demonstrates an association between multiple sclerosis and dog ownership in adolescence – believe that something other than canine distemper virus explains the association. That does not change the fact that their study bolsters the canine distemper- MS theory.

        2. Regarding your latitude point: yes! Thank you!

        “Though distemper occurs worldwide, the virus is readily inactivated by warm temperatures, which would fit with the low incidence of MS in subtropical and tropical areas. Furthermore, Dr. Cook said, in hot climates people are less likely to keep their dogs in the house, and without intimate contact, the dog virus may not spread easily to people.”

      4. There is no evidence for the good Dr Cook’s assertions, the incidence of MS in Australia rather argues against him.

      5. And with that I’m drawing this entertaining little diversion to a close. 😉

        Next week, How MMR is responsible for MS.

  9. Epstein-Barr Virus Vaccine
    The Epstein-Barr virus vaccine in development has been in the works since the early 1990s. An EBV vaccine could potentially prevent infectious mononucleosis, EBV-associated cancers, and multiple sclerosis (MS). A vaccine could also potentially prevent severe illness or even death from EBV infection following transplantation, especially in pediatric patients who have not been exposed to the virus and have no immunity to it.
    Vaccine Mechanism
    Glycoprotein 350 (gp350), an EBV surface sugar protein, is the basis for this vaccine. The prophylactic vaccine will prevent individuals from becoming infected with EBV. The vaccine will work by introducing this gp350 protein to an individual whose immune system will subsequently produce antibodies against gp350.
    How Does the Vaccine Prevent Infection?
    In an unimmunized individual, gp350 has the ability to bind to CD21 receptors on the surface of the B cell and cause viral entry and take over of the cell, leading to infection. Individuals who are vaccinated and have antibodies against gp350 will attack gp350 on the surface of EBV and prevent the virus from binding to the B cells, preventing infection.

    1. I have have questions about the ebv virus and a vaccine

      Does everybody carry the ebv virus or just some people and if you are negative can you then still contract the virus?

      To develop Ms do you have to have actually had full blown glandular fever?

      If the vaccine was released wood only people with a positive reading of the virus be eligible or would those who have already had glandular fever eligible?

      If you already had MS would there be do you think something that could be given to help at that point?,,,,,,,,,,,,

    2. What I meant to say in my question was if you are negative when tested for the ebv virus can you then contract the virus and become positive?

      1. Yes you can catch it in later life. I was negative for EBV until 45 then I caught it. Developed mono/glandular fever for a second time at 50. Gave me Hodgkin’s Lymphoma 4 years after that. Catching it late appears to be bad for you.

  10. Could you list the anti-retrovirals which have been tried against EBV and have failed, or showed promise?
    I can find raltegravir (didn’t work), acyclovir (small trials that showed some effect, or showed no difference, possibly due to more active MS in placebo group), valganciclovir (does inhibit ebv shedding), emtricitabine/tenofovir disoproxil fumarate (Truvada), combivir (observational case study of working in one person), other HAART (reduced incidence in HIV patients).

    Again a straightforward study IF YOU BELIEVE IN EBV would be to test more highly active EBV nucleoside analogs or reactive therapy and not toss the bath water because Raltegravir didn’t work in your hands. 🙁

      1. “Importantly, we found the treatment was safe and without serious side-effects.” – Really? How can they say a treatment is safe based on a first in human study enrolling 10 participants? I hope this was reported out of context because the safety of a treatment generally isn’t established until years after it is registered.

        What should have been reported is the treatment was found to be safe and well tolerated by the 10 participants enrolled to the study for the duration they were followed for safety. Overall safety has not been established.

      2. not really safe to suffer with MS either really is it?

        “years after it’s registered” really tees me off….us with MS have NOT got the luxury of time….imagine the psychological impact of that on top a body that is dropping to bits.

      3. I understand your point. My objection was how the data was reported, that’s all. I’m certainly not saying that allogenic T cell therapy should be abandoned.. What I’m saying is the safety of the treatment cannot be established by administering it to 10 people with MS. The next 10 may fall over dead. I live in Australia and I see these news reports all the time. They give people false hope and downplay the associated risks.

    1. Those drugs you mention are both antivirals and antiretrovirals. The theory behind antiretrovirals is that they inhibit Human Endogenous Retroviruses (HERVs) that becomes stimulated due to EBV infection. You can take any of the two components out to stop the damaging interaction. It is a coincidence that AZT in Combivir inhibits EBV, as there are more than ten case reports of HIV/MS patients on HAART, who are not on the specific drug.

    2. Also, it is already known from HIV experience that in general HAART do not have an effect on EBV, so this is not the case to look for with antiretrovirals.

  11. I just wish this anti-EBV trial success had been around 3+ years ago as I always said that my son’s Hodgkin’s Lymphoma could have probably been cured if he hadn’t had a bad dose of Glandular Fever in his teens. He endured 8 years of chemo, stem-cell transplants etc etc – all to no avail. He eventually died, aged 29, and I still say that EBV was the reason that all attempts at cure failed. I’m not a Doctor but…. oh, how I miss him.
    The trial might come to UK a little late for my MS but my fingers are tightly crossed…I’d love to be at the front of the queue.

    1. Jane: Certain some types of Hodgkin’s Lymphoma are caused by EBV, notably Mixed Cellularity. The virus infects and damages B cells. One of more of these damaged B cells forms the lymphoma.

      I am sorry to hear about your son. I had 8 months of chemotherapy treatment for Hodgkin’s. How he endured 8 years I cannot conceive.

      What is needed is a vaccine so future generations can avoid this pain.

  12. Prof G is it possible that HH6a could be a culprit too? Would this account for some of the variance in RRMS?? Also is there any update on the trial for ATA188 or 190 yet??

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