#ThinkSpeak & #AAN2017: musings on my return from the AAN in Boston

Brain atrophy data in the ocrelizumab extension study was conspicuous by its absence. #ThinkSpeak #AAN2017


My highlight of the AAN 2017 meeting was not MS , but the data on nusinersen (Spinraza) for the treatment of spinal muscular atrophy (SMA). SMA is a severe genetic condition that leads to a deficiency in the spinal motor neuron (SMN) protein as a result of mutations of the survival motor neuron 1 (SMN1) gene. The severity of SMA correlates with the amount of SMN protein, which can be produced from either the SMN1 or SMN2 genes. In a controlled study in which infants (< 7 months of age) with SMA were given nusinersen via a lumbar puncture, or had a sham-procedure, there was a significantly greater proportion of nusinersen-treated motor milestone responders versus sham-control (51% versus 0%; P <.0001). More impressive if infants are given the treatment before they developed clinical disease they developed normally; in other words nusinersen prevents disease

Why are these results so impressive? Firstly, it prevents these children from dying, and secondly it is biology unpacked. Nusinersen is a so called antisense oligonucleotide (ASO) that depends on manipulating how messenger RNA is spliced in order to increase production of fully functional SMN protein; i.e. it switches off production of the mutated SMN1 gene product replacing it with SMN2 gene product. It is a beautiful example of how basic mechanisms can be manipulated to treat disease.

An animated Michael Pender wowing the crowds! 

EBV – As far as MS goes Michael Pender’s work on ‘The safety of treating progressive multiple sclerosis (MS) patients with autologous Epstein–Barr virus (EBV)-specific T cells’ was my MS highlight. He was literally mobbed by people interested in his poster. I was impressed that one senior Pharma executive, who is one of the brightest and most talented in the field, also found this work to be the most interesting. The implications of this work cannot be dismissed and it is very telling that one company will be taking this work forward with allogeneic T-cell lines (Atara Bio). If Michael is correct and the core pathology in MS is senescent, tolerant or burnt-out cytotoxic Epstein–Barr virus (EBV)-specific T cell responses then how do we reconcile this with the current DMTs out there? The latter is the billion dollar question and possibly the ‘Black Swan’ I have been predicting for some time.

Brain atrophy – Alemtuzumab continued to impress with its long-term efficacy data particularly the brain atrophy data (more on this in the future). In comparison, brain atrophy data from ocrelizumab was conspicuous by its absence. There was a platform presentation on the year 3 and 4 extension study of the OPERA 1 & 2 studies in subject with relapsing MS. Ocrelizumab is very good at keeping new lesions from appearing; only 2 subjects out of 700+ subjects had Gd-enhancing lesions in years 3 & 4 and very few had new T2 lesions. However, these metrics don’t get at the end-organ damage that is so important in the long-term to pwMS. 

I have made the case in the past that focal MRI lesions are not MS, but simply form in response to what is causing the disease. If focal T2 lesions were the disease then they would predict a poor outcome regardless of whether or not you are on a treatment; unfortunately, they only predict a poor outcome in pwMS on a DMT. We have already noted that rituximab, ocrelizumab’s mother, may be unable to prevent SPMS. I therefore suspect that ocrelizumab’s brain atrophy data is not as good as alemtuzumab’s and/or HSCT’s. The latter are PIRTs (pulsed immune reconstitution therapies) and differ to anti-CD20 in that they deplete both T and B lymphocytes. Could this be important in their ability to prevent end-organ damage? How does this relate to Michael Pender’s hypothesis above?

I hypothesise that depleting both T and B lymphocytes allows EBV to escape in the periphery, i.e. to replicate or become lytic, and that when the newly proliferating CD8+ T lymphocytes recover they see EBV and mount a new, invigorated, response that reverses the Pender-type senescent, tolerant or burnt-out cytotoxic EBV-specific T cell phenotype. It is the rejuvenation of the latter that results in the long-term treatment effect of PIRTs. In comparison, anti-CD20 simply reduces the EBV viral load in the periphery and do not impact on EBV in other compartments, for example the CNS and cells that don’t express CD20 (plasma cells and possibly glial cells and neurons). The latter provides the reservoir that drives ongoing pathogenic mechanisms and low-grade inflammation within the brain and spinal cord, which results in the ongoing progression. If this hypothesis is correct then the anti-CD20’s won’t be the panacea for treating MS we were hoping for and there will still be a big place for PIRTs in the management of MS. 

The battle ground of the high efficacy DMTs will be played out on metrics that measure end-organ damage and not on upstream inflammatory markers.

It is clear that we know so little about EBV biology in the context of MS. But it is clear that the we are entering an important chapter in the phase of MS research when the MS community is finally beginning to take the EBV hypothesis seriously.

CoI: multiple and I have recently taken on some very exciting consultancy work for Atara Bio in relation to their MS programme. 

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.


  • The claim that "rituximab…is unable to prevent SPMS" is incredibly misleading. Let's look at all of the problems with this claim:
    -The cited study looked at a single patient.
    -Rituximab did not control inflammation in this patient. He continued to develop spinal lesions.
    -The patient was already SPMS/on the precipice at the time of rituximab initiation.

    It may turn out to be correct that anti-CD20 will not prevent SPMS in most patients. This is a reasonable hypothesis. But to already claim that it is "unable" to do so, on the basis of such flimsy evidence, is intellectually dishonest. There is a repeated pattern of the clinicians on this blog (though not the biologists) playing fast and loose with scientific evidence. This does a disservice to the MS community.

    • I agree we need to see the data, Roche probably has folllow up data from the phase II extension. Maybe they could publish it to counter ProfGs claim. Likeswise the Swedes will have rituximab data and I suspect Steve Hauser, which may have been the "horses mouth" for ProfGs comment rather than one paper, based on what he has said previously.

      Although we dont want to plug companies perhaps ProfG can get the immunologic logic on why allogenic cells are sensible as one blogger called it "bonkers"

      The hypothesis is testable given the range of treatments ocrelizimab minor depletion of T, cladribine limited effect on CD8, and alemtuzumab with big effect on CD8 and depeltion of CD8 in year 1 (so look at year 2).

      However based on the animal work depletion of CD8 may be part of the cause of autoimmunity with alemtuzumab, I suspect people are gearing up for a study with anti-CD8 depleters

  • Prof G,

    Thanks for your feedback on the AAN conference. Given the huge number of MS abstracts / posters, it's disappointing that there did not appear to be much (if any) news on neuro-protection / re-myelination or neuro-restoration. I wonder if we are in a lull in terms of new news / breakthroughs. I think Alemtuzumab still has a future. While anti-CD20 drugs are probably less risky, I am more interested in preserving my brain tissue (the thyroid issues are detectable and treatable).

    • There were presentations on anti-LINGO most of the studies are either pre-clinical or are ongoing

  • Strange given roche has been banging the drums for ocrelizumab why would they not release brain atrophy stats? Are they worried about being compared to alemtuzumab?

  • This EBV-specific T cell thing is interesting, very interesting. This has the aura of something really special around it. Thank you for reporting/informing on this.

  • Thanks for the feedback from the AAN.
    If I've understood things correctly then EBV seems a critical focus as to the cause of MS and plays a role in the on-going damage?
    May I ask: is there any focus on EBV and other conditions that maybe beneficial as to the understanding of the role of EBV? Only, as I've mentioned before, my sister has Sarcoidosis, where I have MS and we both had glandular fever as teenagers. On a number of occasions her medical team have exclaimed at the number of EBV antibodies present, when she has blood tests, even though she is not presenting with glandular fever. Guess I can't help but wonder if an expansion of the focus would provide so much more of the jigsaw???

  • Hi,

    Are saying that b cells (or some types of them) do something that causes or leads to t cells attacking the ebv virus and turning into ms damage t cells?

    If you kill off just the b cells, you are left with t cells that remember ms.

    If you kill off t and b cells (or enough of them in a short period), then there is nothing to tell the t cells to be ms like and attack. If you kill off the t and b cells with a PIRT then the t cells come back without the ms memory. Before the new ones get memory of ms from the b cells mechanisms, then that could be the reason for the longevity of the PIRT treatment.

    I know it's a theory, but is my understanding right?


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