HSCT is shifting the Bell curve

Barts-MS rose-tinted-odometer  ★ ★ ★

The good news is that the use of autologous HSCT to treat autoimmune diseases rose (by 19%) in the European Bone Marrow Transplant registry in 2018. Importantly, this rise was predominantly due to HSCT treatment for multiple sclerosis. This would indicate that at least at the very right of the bell curve there is increasing use of a more aggressive approach to treating MS. If this indicates that the bell curve has shifted to the right it means that more pwMS are being treated with highly effective treatments and I suspect that many are getting onto these as first-line therapies. 

What will this mean at a population level? I suspect that over time the prognosis of MS will improve and an increasing number of patients treated with IRTs (cladribine, alemtuzumab and HSCT) will be rendered free of detectable disease in the longterm. If and whether we will be able to claim that a proportion of these pwMS are cured of having MS will depend on the MS community coming up with a widely accepted definition of what an MS cure looks like. 

How IRTs actually work will remain a moot point. Immunologists will claim that they deplete pathogenic autoimmune T and B lymphocytes and reset regulatory immunological networks. Proponents of the EBV hypothesis will claim they all work by targeting pathogenic memory B cells that harbour EBV. Sorting out these competing theories will really require targeted EBV studies, the sort that has been developed by Atara Bio. Another strategy will be using anti-viral agents active against EBV; this will include both existing and new anti-EBV therapies. 

If I have to bet on the outcome I would favour the EBV hypothesis. There are simply too many holes in the autoimmune theory of MS and the epidemiology backing EBV as the cause of MS is now so overwhelming that the wider MS community is finally getting behind EBV vaccination as a possible preventive strategy. I hope you agree.

Passweg et al. and the European Society for Blood and Marrow Transplantation (EBMT). The EBMT activity survey on hematopoietic-cell transplantation and cellular therapy 2018: CAR-T’s come into focus. Bone Marrow Transplant. 2020 Feb 17. 

Hematopoietic-cell transplantation (HCT) is widely used for acquired and congenital disorders of the hematopoietic system. Number of transplants performed in Europe and associated countries continues to rise with 47,468 HCT in 42,901 patients [19,630 allogeneic (41%) and 27,838 autologous (59%)] reported by 701 centers in 50 countries in 2018. Main indications were myeloid malignancies 10,679 (25%; 97% allogeneic), lymphoid malignancies 27,318 (64%; 20% allogeneic), solid tumors 1625 (4%; 2.9% allogeneic), and nonmalignant disorders 3063 (7%; 81% allogeneic). This year’s analysis focuses on cellular therapies with the marked growth in CAR T-cell therapies from 151 in 2017 to 301 patients reported in 2018. Other cellular therapy numbers show less significant changes. Important trends in HCT include a 49% increase in allogeneic HCT for chronic phase CML (although transplant numbers remain low) and a 24% increase in aplastic anemia. In autologous HCT, there is an ongoing increase in autoimmune diseases (by 19%), predominantly due to activity in multiple sclerosis. This annual report reflects current activity and highlights important trends, useful for health care planning.

CoI: multiple

21 thoughts on “HSCT is shifting the Bell curve”

  1. Interesting. A couple of points: PwMS are not ‘subjects’ to be cured but real people or participates if in a study. Let’s leave the subjects to the mouse doctors.
    But also, I’d love to hear your thoughts on IRT comparatively. To me (who doesn’t know a heap about them) it seems fascinating as to why you’d opt for Invasive HSCT over an oral… have you written on them comparatively somewhere?

  2. Great news !!
    It’s a pleasure reading your lines and I totally agree with them !!
    We must be hard on MS, I have MS since August/2000 and just ended R2 of Alemtuzumab, I wished that it would come sooner!!

  3. Prof G,
    Thanks for this post.
    “If I have to bet on the outcome I would favour the EBV hypothesis. There are simply too many holes in the autoimmune theory of MS and the epidemiology backing EBV as the cause of MS is now so overwhelming that the wider MS community is finally getting behind EBV vaccination as a possible preventive strategy. I hope you agree.”
    I’m sure many of us agree. Is there anyone working on the EBV angle i.e. working on a vaccine or doing other stuff (the only person I hear about is Professor Pender). Is your lab doing any work in this area?

  4. Is it possible that EBV somehow triggers an autoimmune response? Similar to how a strep infection can trigger some psoriasis, and I think there have also been infections potentially implicated in rheumatoid arthritis.

    1. The implication is that the T cells are reacting to EBV viral antigens presented by immortalized B cells. The antigens are being cross presented by neurons which may also be infected, leading to destruction of the neurons which is your autoimmune response. EBV infection is for life as well, so you can’t sterile-ly cure it as it will hide in B cells that don’t replicate forever. Atarra changes the T cell response to the focus on the lytic cycle rather than latent cycle antigens- possibly it is latent antigens being presented by neurons. An IRT may also reset the T cell response against EBV infected B cells if somehow the imbalance between latent/lytic T cell recognition is what is causing things. SPMS or PPMS would be predicted to be the EBV lytic cycle killing off neurons without a lytic focused immune response there to stop it if this theory is correct.

      Smoldering mono?

  5. My happy idea is that EBV is necessary to immortalize B cells and thus escape the control of regulatory T cells. These immortalized B cells react to some molecules that mimic myelin molecules. It can be L-fucose sinthase, HERV ENV, … that is why Pender’s study with CAR-T will work in all cases of MS and GeNeuro temelimab will only work in those in which MS is caused by HERV-ENV .

  6. So much going on in the remyelination space:



    I understand that Dr Coles & co are refocusing from anti-inflammatories to remyelination building on the work of Prof Franklin.

    If Team G could crack the smouldering MS issue and the others could deliver something on remyelination we could have the start of a new dawn in how MS patients are treated. I recently saw a piece about research / trials to encourage spinal cord repair.

    1. Good to see tha the JK Rowling money has gone some where, I was worrying that Edinburgh had not done anything with all the money

    2. Working on remyelination…yes that is what I have heard.

      You wish is the MS Societies command….Watch this space

      We could have the a new dawn…but we have to move against the inertia of monotherapy trials and need to do these studies on top of inhibition of peripheral immunity, if not we miss a trick

  7. Can we have some more information on remyelination? As someone with PPMS and is on an IRT already, some good news on this would be welcome, or is the majority of the clinical effort on stopping disease activity rather than adressing damage already done.

  8. Interesting….thank you. So are you saying you don’t believe ms is an autoimmune disease? Because I don’t. When I first became unwell in 2011 my EBV titres (sp) were very high. No general consensus on ppms and hsct huh?

  9. I am extremely pleased to read that EBV is finally coming into focus and autoimmunity is being critically questioned. Thank you for that!

    I just hope that it won’t lead to the same mistake, in thinking there’s always only one cause. After reading countless MS studies over the years, I think MS might also develop as a result of other chronic infections. EBV might be the most prominent one, but other viruses could also be responsible.

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