#ECTRIMS2021: EBV as a therapeutic target; another Lazarus effect?

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Barts-MS rose-tinted-odometer: ★★★★★★
(6-stars calls for a bright orange Thursday, #FFA500)

As you are aware by now I  am one of the people in the field of MS who thinks EBV is the cause of MS. My position is essentially based on epidemiological evidence and causal inference. At the moment I honestly don’t know how EBV causes MS, but one hypothesis is that ongoing EBV infection in the CNS or in a peripheral compartment drives MS disease activity. EBV resides in memory B-cells and memory B-cell appears to be the main target of all effective MS disease-modifying therapies. 

The question is can we simply treat MS  by targeting EBV and not using a sledgehammer; i.e. depleting all B-cells (anti-CD20) or taking out the memory B-cell with non-selective immune reconstitution therapies (IRTs), e.g. AHSCT or alemtuzumab? One way to do this is to use anti-EBV drugs or cellular therapies targeting EBV infected cells. 

This is why one of my highlights at this meeting is Atara Bio’s phase-1 MRI data on using anti-EBV HLA-matched cytotoxic T-lymphocytes as a treatment for progressive MS. Study subjects who had sustained improvement in the EDSS showed a significant increase or improvement in their brain MTR (magnetization transfer ratio) at 12 months compared to baseline. MTR is an MRI marker of tissue integrity and is thought to represent tissue repair and remyelination. The important point for me is the MTR is an objective measure done using software and is blinded to the clinical information or treatment allocation. Having an objective measure on MRI that correlates with a relatively subjective clinical measure improves my confidence that what we are seeing may be real.

The other remarkable observation in this study is by how much some of the responders in this study improved. EDSS scores improved by well over one EDSS point with one patient improving by as much 2.5 points, i.e. from an EDSS of 5.5 to 3.0. Two other subjects went from EDSS 6.0 to 4.5; from needing a walking stick to walk 100m to be able to walk between 300m and 499m unassisted and without taking a rest. Outside of relapses, these sorts of EDSS improvements don’t happen in people with established progressive MS. This is almost as impressive as the Lazarus effect we see rarely in patients treated with steroids or plasma exchange for a relapse. The Lazarus effect describes those patients who go from EDSS 7.0+ (bed-bound) to getting up and walking within hours to days of being treated. 

Note: Lazarus of Bethany, also known as Saint Lazarus, or Lazarus of the Four Days, venerated in the Eastern Orthodox Church as Righteous Lazarus, the Four-Days Dead, is the subject of a prominent sign of Jesus in the Gospel of John, in which Jesus restores him to life four days after his death (source Wikipedia). 

The following are heat map tables from the poster in the patients who improved and those who didn’t improve. Green being an improvement and red is no improvement. Even in the so-called non-responders, some study subjects improved.  

The good news is Atara’s product is now in phase 2 as part of a blinded study and if it clears this hurdle a large phase 3 programme is planned. Prior to this data emerging my odds of this strategy working in MS would have been way below 50%; actually in the order of 2-5%. Now with objective MTR data correlating with such dramatic clinical improvements, my predictions have soared to now being above 50%, i.e. in the order of 50-67%. 


Pender et al. Updated open-label extension clinical data and new magnetization transfer ratio imaging data from a Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive multiple sclerosis. ECTRIMS 2021, P368.

Introduction: Mounting evidence suggests Epstein-Barr virus (EBV) is a necessary risk factor for development of multiple sclerosis (MS) [Abrahamyan et al. JNNP 2020]. Early experience with autologous EBV-specific T-cell therapy proved safe and may offer clinical benefit [Pender MP et al. JCI Insight 2018; Ioannides ZA et al. Front Neurol 2021].

Objectives/aims: Evaluate the safety and potential efficacy of ATA188 in adults with progressive MS in an ongoing open-label extension (OLE) study, including an imaging biomarker: magnetization transfer ratio (MTR).

Methods: In part 1 of this 2-part Phase I/II study, 4 cohorts received escalating doses of ATA188. Patients (pts) were followed for 1 year and could participate in a 4-year OLE. Sustained disability improvement (SDI; including expanded disability status scale [EDSS] and timed 25-foot walk), as well as safety, were measured [Pender MP et al. EAN 2020]. As a biomarker of improvement, change from baseline in MTR, an exploratory endpoint, was assessed.

Results: 25 pts received ≥1 dose of ATA188 and were followed for up to 33 mos (m). No grade >3 adverse events (AE), dose-limiting toxicities, cytokine release syndrome, graft vs host disease, or infusion-related reactions were observed. 2 treatment-emergent serious AEs were previously reported (muscle spasticity [grade 2; not treatment related]; MS relapse [grade 3; possibly treatment related]) and, as of April 2021, 1 was reported in the OLE (fall; grade 2; not treatment related). Efficacy was evaluated in 24 pts in the initial 12m period and, as of April 2021, in 18 pts in the OLE followed for up to 33m. 9 pts met SDI criteria either in the initial 12m period (n=7) or in the OLE (n=2); of these, 7 had sustained EDSS improvement. Of the 8 pts that achieved SDI and entered the OLE, 7 maintained SDI at all subsequent timepoints. Pts with sustained EDSS improvement (vs those without) had greater increases in MTR signal (in unenhancing T2 lesions and normal-appearing brain tissue) at 12m.

Conclusions: Preliminary data indicate ATA188 is well tolerated. Sustained EDSS improvement drove SDI in most pts, and in all but 1 pt, SDI was maintained at all subsequent timepoints. As a biomarker associated with disability, pts with sustained EDSS improvement (vs those without) showed greater increases in MTR signal at 12m, which may be suggestive of remyelination. The Phase 2 portion of this study, EMBOLD (NCT03283826), is ongoing and currently enrolling.

The following is Atara’s press release if you want more information. 

ATA188-ECTRIMS2021-PR_FINAL

Please note that I am a consultant to Atara and sit on their EBV/MS advisory board and advise them on their clinical development programme. 

Conflicts of Interest

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

47 comments

  • The start of the phase 3 trial is near for ebv. The estimated completion date for the phase 2 of ata188 is at the end of 2022 or beginning of 2023.

    How are things going with Moderna in terms of the collaboration for the therapeutic vaccine for ebv ?

    • We are talking with Moderna but their EBV vaccine is behind their cMV vaccine in priority and it needs to be tested in phase 1 first.

      • Can CMV play a role in MS, would the vaccine help people with MS, EBV maybe a major player / cause but other uncontrolled viruses maybe at play?

        If the immune system can’t fully control EBV for example is it fair to say it can’t control other viruses also?

      • Good to hear that discussions are ongoing. Sure but like their flu vaccine Stéphane Bancel ( ceo of moderna ) mentioned it will not take 5 years to make one. They mentioned less than 5 years for their flu vaccine so I suppose the timeline for the ebv Therapeutic vaccine could be in the 5 year mark range maybe a little less maybe a little more but given their expertise I would say : within 8 months the start of the phase 1 trial for their therapeutic vaccine for ebv 9 months to have a good idea of safety ( like they did for their cmv vaccine ) which would initiate a phase 2 trial lasting about 1 year and finally 2 years to complete a phase 3 trial for relapsing ms. So about maybe 4 to 4 and a half years for the therapeutic ebv vaccine.

      • Where do I sign up? The important thing is not to get put in a placebo controlled trial where a 1:2 improvement would be reduced to 1:4 by the half getting placebo.

      • Hi Prof G,
        Are you saying 1 in 2 to 2 in 3 pwMS would react to EBV targeting therapy? Or the odds are referring pathologically it would work?
        Thanks!

  • Addendum. Didn’t have time to add that I do realise much more research needed (as I was on the sleeper train and my stop was imminent).

  • Add I see my hasty addition on the night train hasn’t materialised. I wrote that I hope this supports your EBV hypothesis and that I was asking how long before this sort of work benefits pwMS. How will it feed into NICE’
    s decision making in future? There seems to be a different approach to pwMS, cf., say, cancer, where the strategy is treat, treat, treat, ASAP. It seems as if NICE is not concerned about deterioration in MS. Is that a fair comment?

    • Kit, this is still on phase 1. It needs to get through phases 2 & 3 so many years away from the clinic that is if it gets to the clinic.

  • This appears to vindicate your hypothesis of EBV being a causal factor. If so, how will this affect psMS into the future and when will it feed intoNICE?

  • I haven’t read the press release yet but I suppose it is too much to ask that wheelchair-bound people 7.5 will be included in the trial?

  • This feels dangerously close to hope, and it makes me both excited and scared. Fingers crossed that you’re right in your prediction and it works

  • “At the moment I honestly don’t know how EBV causes MS”. I was going to ask what the hell you’ve been doing for the last 30 years! I’d suggest more time in the lab and less time producing pamphlets / leaflets / tube maps.

    Can EBV reside in actual tissue cells (rather than just B cells) ie brain tissue cells? Is it not feasible that EBV gets into the CNS and infiltrates CNS tissue? Then the tissue cells get sick / die off and there is an immune (first within the CNS and then the peripheral immune system gets involved) response causing more damage. Until the root cause of MS (chronic EBV infection) is addressed the treatments targeting the immune response are just pissing in the wind ie the real MS continues. causing damage. You know this from the B cell depletes – they don’t stop progression in the long run.

    • Sid, you know what I mean. Is EBV simply a ‘hit-and-run’ effect, i..e does it simply trigger autoimmunity and then once that happens to target EBV after you have MS is too late or is EBV driving the disease process? I suspect the latter.

  • I had a Herpes infection in my eye for a number of years as a child, took numerous operations to remove the growths. I often wonder if this was the trigger that started my MS as looking back I have had symptoms from my teenage years but wasn’t diagnosed until 29. Would love to participate in this trial, pity there are no centres in the UK. Very excited to see where this research goes!

  • Lots of “Hub-Bub, Bub” is going to surround this one. Some trials are stopped early because results are so convincing and it is in the best interest of placebo controls and those affected in society, to hurry things up. Any chances of that here if things were to go well? (For those seeking to volunteer, you have to be less than 61 yrs 🙁 But + phase 1 included up to 65 yrs, so there is “hope” for the older set as well. If we just didn’t have to wait so darn long).

  • Black Swan!!! Those two words made me look up. I am geeking out in the science now & all because of a word choice in the title. This could be crazy amazing….

    My neuro said it is EBV in my very first meeting with him. You’ve given me something to discuss in my next clinic visit.

    Thank you for posting this one & I appreciate your conflicts of interest disclaimer.

  • As ever the MS societies are funding the wrong targets. The U.K. MS Society is raising £100m to Stop MS. No mention of a viral cause of MS. Instead they will fund the Octopus trial which will trial various chemicals in the hope of providing neuro-protection or remyelination. Don’t hold your breath. Remember the Smart MS trial – 3 drugs and 3 failures. Why not use some of the money to fund a HAART trial of 25 people with MS? No safety trial (we know it’s safe), no placebo arm (if the effects are good enough it will be obvious). There needs to be a shift on what MS drug trials are targeting and a shift to the patient (is a placebo arm moral?) rather than academic requirements.

    As patients we need to get more vocal / aggressive – MS academics have not delivered and are mainly focused on the immune system response (which is not the cause / driver of MS). Neuros are Neros – happy to twiddle their thumbs while our brains burn. I’m sure the MSologists are enjoying ECTRIMS 2021. Does anything ever really change for MSers as a result? Has it really taken 50 years of MS research to work out that EBV is the cause of MS? Scandalous. Mice don’t get EBV, so EAE has steered the research down the wrong road for decades. Time to ditch the furry little harmless rodents, shift from the obsession with the immune system (a response), and get virologists / EBV experts on the case. Yes, I know Prof G and MD1 are nice guys etc, but niceness isn’t stopping the disease in its tracks. Thank you Prof Pender for your dedication – a real hero willing to look at something different rather than follow the MSologist lemmings with their T cell v B cell obsession which has not stopped progression / increasing disability.

    • EBV resides in memory B-cells and memory B-cell appears to be the main target of all effective MS disease-modifying therapies.

      Identified for the first time by MD1 after much hard work and dedication way, way beyond the call of duty in dragging the data out of pharma. Let us not forget that.

    • Agreed saying there going to stop MS etc, its just looks like total bullshit

      Maybe to someone who doesn’t do any digging into MS or even read this blog for example.

      The treatments, if found successful in the octopus trial won’t even be prescribed to people with MS, they don’t advertise that on the website.

      I’m sure they do a lot of great things but they need to be honest, transparent and factual.

    • We do need to raise our concerns and our desire to move the ebv therapeutic strategy goalpost forward.

      Asking what your ms society is doing to move these strategies forward is one way.

      Another way is to sign a petition saying we want more trials targeting ebv with enough individuals to be statically significant to move this goalpost forward.

  • Does this reinforce the idea of taking some natural anti-EBV compounds like Quercetin or Andrographolide as dietary supplements?

    • Not really, who knows whether either of those supplements would even have an effect on EBV outside of petri dishes, or what dosage you would need to see the effect, or whether they can enter the CNS, etc.

  • This aproach is the same as car.t cells ( in this case Ebv infected cells 9

    One of the problems car-t cell faces is t cell fading away and disease recurence

    How is this problem sort out by atara?

    Obrigado

  • Have they tested the anti-EBV response of the non-responders? What are their conditions for passing the clinical product for infusion? If it is just “we need 1e8 cells per person” without at least some sort of demonstrative ELISPOT or cytokine anti-EBV response, that’s a bit worrisome. One problem may be that non-responders don’t have the correct matchup of HLA molecules to support a robust anti EBV response, or their central tolerance has eliminated the possibility of that response. No amount of ex vivo culturing may be able to recover that response. Unless you go with 3rd party cells.

    There is a yet-to-be funded trial of an anti EBV antiviral Tenofovir Alafenamide NCT04880577 that is waiting for some green to start up. While the anti-EBV T cell therapies are great, their cost would likely be enormous compared to even current monoclonal antibody therapies. I still believe getting the Truvada drug as a pill targeting EBV replication would work.

  • I have slow PPMS and have always felt that what was driving my MS was some kind of virus. I won’t blether on about my unsubstantiated reasons why. But I am both heartened to read this post and very disappointed that I will probably see no therapy in time for me. And many others.

  • I’ve read that tenofovir is a potent EBV antiviral, so shouldn’t we also see this in people taking Truvada/Descovy for HIV prevention? I would think there should be a huge population of people to observe this in.

    • Well that’s the point of the previous research study looking at patients on HIV medicine and their reduced incidence of MS

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283699/

      Dr. Giovanni was an author on that- reducing the rate ratio to 0.38 is a substantial drop in cases. You have a hypothetical argument about reduced activity of T cell activity in HIV patients, but the whole point is that these patients are on HAART retroviral drugs so their T cell numbers aren’t bottomed out. The actual frequency of MS cases even in cohorts of 20k HIV patients is still only 7 observed vs 18 expected. But that’s what statistics are for to extrapolate. That and phase I/II studies to test the theory in actual MS patients (whcih is what the Tenofovir study is proposing to do- ocrevus RRMS patients).

      It’s very frustrating the researcher can’t get funding for it.

      • Yeah that really is frustrating. There is a sizable population, myself included, that are already on truvada/descovy for HIV prevention. It would be interesting to look at the subset of us with MS to see how we differ. I’m only one individual, but my MS has always been astonishingly mild, glacial even.

          • I was diagnosed 14 years ago, for the first 11 years I was on no medication. I started taking medication after my first relapse 11 years later. I tried Gilenya but it suppressed my immune system too much, then Abagio but had elevated liver enzymes, then rituximab until covid hit and now I’m holding off until that shakes out. I’ve been on Truvada since the FDA approved it for PrEP in 2012.

  • What can I say. I learn more about EBV when husband got Lyme, then doing my own research I start suspecting that EBV caused MS

    Summary: not only but also
    Me and My mother both have MS and both have EBV!

  • This looks spectacular. Will have to read the paper over the weekend. Can we please please please have study site in Europe?

    Looking at the few approved CAR-T therapies and what goes into making them, I fear this one will be uber expensive though. Reassuring that they didn’t have any cytokine storms, either.

    Just read about EMBOLD. Given the patient selection criteria (basically the group nobody otherwise dares to touch….), name checks out.

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