Memory B cells as a central target for relapsing MS. How much more evidence do you need?

M
reduction of relapses after rituximab treatment

A few days ago we had the the effect of ozanimod on lymphocyte subsets and whilst T cells subsets were examined, B cells subsets were not…I said how can you understand how ozanimod works if you do not look at memory B cells.

Sadly this view falls on deaf ears or is that blinkered eyes

We made the point that all agents that inhibit MS also inhibit memory B cell activity. So far we have yet to see data that argues against this. When it does I will modify my view.

Ocrelizumab and rituximab selectivly target B cells. These are dosed every 6 months but we have made the point that if you consider memory B cells to be important targets then based on their repopulation kinetics, you should not have to dose every 6 months in everyone. We showed that based on the ocrelizumab phase II study. It is shown again here. Rather than dose every six months, the re-dose occurs when the memory B cells reach a set level, This way they can keep people in remision, whilst reducing the dose-requirement.

This now says the same as neuromyelitis optica, rheumatoid arthrits, myasthenia gravis, etc, etc, etc ,

If we can find the pathogenic cell characteritisics one could refine this further, but at some point I suspect we can stop the dosing and ocrelizumab becomes like alemtuzumab.

Tailoring B cell depletion therapy in MS according to memory B cell monitoring.Novi G, Bovis F, Fabbri S, Tazza F, Gazzola P, Maietta I, Currò D, Bruschi N, Roccatagliata L, Boffa G, Lapucci C, Pesce G, Cellerino M, Solaro C, Laroni A, Capello E, Mancardi G, Sormani M, Inglese M, Uccelli A.Neurol Neuroimmunol Neuroinflamm. 2020 Aug 4;7(5):e845. doi: 10.1212/NXI.0000000000000845. Print 2020 Sep.

Objective: We wanted to evaluate efficacy on inflammatory parameters of rituximab (RTX)-personalized reinfusion scheme using a memory B cell-based treatment regimen.

Methods: This is a prospective, uncontrolled, open-label study including patients with MS treated with RTX in 2 Italian MS units. All patients were treated with RTX induction, followed by maintenance infusion at the dosage of 375 mg/m2, according to memory B cell repopulation (0.05% of peripheral-blood mononuclear cells [PBMCs] for the first 2 years, 0.1% of PBMC for the third year). MS activity was assessed as clinical or MRI activity.

Results: One hundred two patients were included in the analysis. Mean follow-up was 2.40 years (range 0.57-7.15 years). The annualized relapse rate (ARR) was 0.67 in the year before RTX start and decreased to 0.01 in the 3 years after RTX initiation (global ARR). The proportion of patient with MS activity (i.e., relapse or MRI activity) was 63.16% in the year before RTX start and decreased to 8.7% (0-6 months), 1.3% (6-12 months), 0% (12-24 months), and 0% (24-36 months). Annualized RTX infusion rates were 1.67 (95% confidence interval [CI]: 1.43-1.94), 0.76 (95% CI: 0.58-0.98), and 0.78 (95% CI: 0.52-1.12) for the first 3 years after RTX initiation, respectively. Patients were reinfused with a mean infusion interval of 367 days (range 181-839 days).

Conclusion: The results of this study show that the memory B cell-based RTX reinfusion protocol is able to reduce the mean number of RTX reinfusions with persistent reduction of disease activity.

About the author

MouseDoctor

20 comments

Leave a Reply to Dan Cancel reply

  • Have you considered immune memory x cell type is the culprit? A changling that activates both T and B cells, thought to exist but only recently discovered. Would explain why b cell only therapies fail to reduce brain atrophy as effectively as Alemtuzumab. Also why be disappoonted at the ozanimod study. Give all barts ms patients being treated with dmt, blood tests to check the number of memory b cells. And its just a one time cost. But may win barts the noble prize for medicine.

    • immune memory x cell type is the culprit?…It is obviously a subset that needs definition but why consider a new cell when we have not done the easy stuff.

      https://multiple-sclerosis-research.org/2019/01/not-all-data-is-created-equal-brain-atrophy/

      B cells and atrophy..please read the blog. Please please please can any swedish neuro reading the blog answer this question?. What is the atrophy rate 2 years after treating with rituximab from diagnosis

      Check all MS patients blood levels….I wish…but this needs ethics and resource, and getting
      ethics to do this. We will be looking at cladribine.

  • But are MS relapses the disease we call MS or are they simply the immune system’s response to what is causing the disease?

    I would argue that relapses and focal MRI activity are not MS and that the real disease is smouldering MS, which is why anti-CD20 therapies are so poor at reducing end-organ damage and preventing the inevitable development of secondary progressive phase of the disease.

    Interesting that all of the Pharma companies that have an anti-CD20 therapy in their stable of MS products have active ongoing research programmes to find better therapies to manage MS. Why? Because these companies know anti-CD20 therapies are not really the answer to managing MS. Their decisions are data-driven, i.e. driven by their own data.

    • OK, but can you explain the mechanism by which Alem and Natalizumab address smouldering MS more than OCR? In my understanding, they don’t really penetrate inside the CNS (not more than anti CD20) and they act mostly by controlling the peripherical immune cells in order to avoid them going inside the CNS (by killing B cells for OCR, B & T cells for Alem, or preventing them to get inside the CNS for Natalizumab)

      MD argues that the difference of BVL between Alem and Ocr can be explained mostly by the age difference of pwMS in the clinical trials (2 years for Alem in mean compare to 6 years for Ocr). It’s only another hypothesis but can we really know without making a trial comparing Alem and Ocr directly?

      What make you think MD is wrong?

      • Alemtuzumab targets a newly discovered self reactive immune memory cell x type that activates both t and b cells in a feedback loop making it the most potent immune cell. Breakthrough was made in diabetes type 1. Beta pancreatic cells do not bind MHC receptors on B memory cell if autoimmune diseases were b cell mediated. Im going to let barts do the rest of explaining. Ps x cel type was discovered by machine learnong simulations of the immune.

      • Re: “Alem and Ocr can be explained mostly by the age difference of pwMS”; up to age 55 there is very little difference in the rate of brain volume loss in relation to age. It is only after age 55 that it accelerates. The HSCT cohorts challenge the age brain volume loss argument; for example, the Canadian cohort was about 6 years into their disease.

        It doesn’t really matter if you are able to choose your own treatment; you can be treated with an anti-CD20 and I will choose alemtuzumab, or preferably HSCT, and we see who is better off in 20 years time. The problem is when you get to 20 years time you can’t change what has happened over the last 20 years 🙁

        • Hi, Prof G. Thanks for your reply. Hope you had a great holiday.

          Good for you (even if you don’t have MS) but sadly we can’t choose Alem in most country and you know it. It’s even difficult to get anti-CD-20 first line witch I managed to have even so.

          I just try to understand everything I can about MS, that’s all. And, as a scientist, when I don’t understand something I read (and again thank you so much for this blog) I just try to get some answers, especially when there is scientific controversy.

          ‘up to age 55 there is very little difference in the rate of brain volume loss in relation to age’ for healthy individual OK, but are we sure of that in pwMS ?

          • The MAGNIMS consortium has shown in a study of almost 1000 pwMS that the average brain volume loss is of a similar rate in patients with CIS, RRMS, SPMS and PPMS. The progressive patients are much older than the CIS and RRMS patients.

      • 🙂
        What makes the difference yep DATA

        CLADRIBINE
        CLARITY DATA 9 years after MS= 0.4 atrophy rate
        ORACLE DATA before MS = 0.2 atrophy rate

        Rituximab. The Brain parenchymal fraction (brain volume) was reported as -0.19% assessed in 160 pwMS (Salzer et al. Neurol 2015)

        Prof|G says
        “Interesting that all of the Pharma companies that have an anti-CD20 therapy in their stable of MS products have active ongoing research programmes to find better therapies to manage MS”.

        Alternative view

        (a) Any company that has an MS drug is looking to find better thereapies because they are looking what happens when their patents run out. When patents run out their cash flow reduces.

        So Fingolimod becomes siponimod, Avonex (one a week interferon) becomes Plegridy (one every two weeks interferon), Glatiramer acetate 20mg daily becomes 40mg thrice weekly. Rituximab becomes ocrelizumab

        (b) It seems no company has been rushing in to a combined T and B cell depleter even Genzyme/Sanofi dropped their new CD52 project so maybe they don’t think brain atrophy is a useful indicator

        (C) Better therapies
        ROCHE MS pipeline? Rituximab to Ocrelizumab what next?

        https://www.roche.com/research_and_development/who_we_are_how_we_work/pipeline.htm………..Nothing specifically for MS

        NOVARTIS: next in pipleine Ofatumumab
        GENZYME: Alemtuzumab…what next a B cell (BTK) inhibitor
        MERCK: B (BTK) cell inhibitor
        BIOGEN: B (BTK) cell inhibitor
        ROCHE: B (BTK) cell inhitior

        If we think CD20 data is bad then based on data the BTK data from Merck which does not seem any better and probably worse then we are in for a shock.

        Also in Roche pipeline The son of daclizumab

        Autoimmune diseas. RG7835 is a conjugate of human IL-2 and IgG (fused IL-2 mutein). IgG–IL2 preferentially stimulates and expands T regulatory cells but not T effector cells…How does this work increase CD25 T regs…but no CD25 activated T cells or CD25 memory B cells .

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284106/
        Memory B cells not tested an increase in T cells at higher does and a massive increase in CD56 high NK…so Daclizumab like and we all know what happened there…….Will it get to phase III

        If Pharma have the data then the neurologists working wih Pharma have a duty to bring the negative data to light.

        Iran or Sweden have the data of early treatment data

        • Thanks, MD and Prof G. I don’t know who is right but it’s exiting research anyway!

          Maybe we can compare this two ideas with your clinical data at Bart MS? What about your patients treaded early by anti-CD-20? Do you have some BVL data?

          • We dont use rituximab and not sure with ocrelizumab is we have brain volune data…maybe profG K can do an audit

        • Mouse,

          If you and Prof G can’t even agree, what chance do us MSers have of getting really effective treatments? It’s like watching an episode of the Chuckle Brothers – “to me, to you”.

          https://www.youtube.com/watch?v=kEOkg6-FmJ4

          Without an agreement on what is driving the disease, trials designed by Team G are just pxxxing in the wind.

          Perhaps the MS researchers (Team G) should just throw their hands in the air and admit defeat. Otherwise we’ll be going round the same old buoys for another decade. We need some Young Turks to take MS research forward.

          • What is the chane of getting effective treatments…it depends on what pharma do what does. Haven’t you got that yet…You can moan at us because we have given you a soap box, I don’t see you having a dig at Cambridge, Oxford, Edinburgh, Queen square, Havard, Stanford etc etc for their outputs. Your record has stuck…and it is tiresome… As my father said, when he thought i was talking (asking questions) too much…”Give your arse a chance”

            I’ve been farting ever since:-)

            Why do you think we are disagreeing…on the idea that there is something in the CNS driving the disease I have no issue with that, all I am questioning is the data on which the assumption is made..and as for not having the same views it shows that we can debate and adapt, ProfG throws out more ideas than a jugler…the key thing we have to do is to decide which balls to catch and which ones to let fall on the ground.

            As for smouldering MS, I have had ideas for years but unless a clinician or pharma want to do it it doesnt happen…why do you think we are still doing monotherapy trials?

            Trials designed by TeamG is pixxing in the wind.
            Do you honestly think I can have any influence on what the pharmaceutical industry does in a trial…If you do, then you are dreaming and deluding yourself….ProfG may advise on some trials, but do you think he actually decides what is done? These are commercial decisions made by the companies, if they dont want to do it, it doesnt happen, if they think your advice is valuabl, they may do it.

            Next as someone working on animals models of a uniquely human condition, is thinking about something that does not happen in animals going to be the most useful use of one’s time?

  • immune memory x cell type is the culprit?…It is obviously a subset that needs definition but why consider a new cell when we have not done the easy stuff.

    https://multiple-sclerosis-research.org/2019/01/not-all-data-is-created-equal-brain-atrophy/

    B cells and atrophy..please read the blog. Please please please can any swedish neuro reading the blog answer this question?. What is the atrophy rate 2 years after treating with rituximab from diagnosis

    Check all MS patients blood levels….I wish…but this needs ethics and resource, and getting
    ethics to do this. We will be looking at cladribine.

  • Evidence is enough for me: data are speaking loud and clear.

    The real MS… we have memory b cell driving relapses and we can shut them off but damage still occurs. What is left that can elicit immune response and damage? Innate immunity and complement. What can activate them? Foreign invaders and antibodies. We have not been able to find the invader but we found antibodies. So, to me it would make sense to first target antibody production, we know they are there and they should not be. Let’s kick them out. But not as single target. If we get rid of antibody we will leave memory b cells free to replicate and make new plasma cells that can make antibodies that restart the loop: they trigger the response and the autoimmunity is restored. We may get to the starting point and say that it worked but only for few years… it would not be The Solution. So, I would say and bet on peripheral depletion of B cell lineage (CD20 or CD19 may be even better), CNS depletion of B cells (cladribine unless there is something else) and then targeting plasma cells (proteasome inhibitors, antibodies…?). Basically, I would bet on Barts trial but maybe on steroids.

    Somebody did that for cancer.
    https://clinicaltrials.gov/ct2/show/NCT00980395?term=Cladribine&draw=2&rank=22
    https://pubmed.ncbi.nlm.nih.gov/29056470/
    https://clinicaltrials.gov/ct2/show/NCT01439750?term=Cladribine&draw=2&rank=25 the status of this is unknown

    Oncoematology papers are a source of potential treatments. There are interesting papers on multiple myeloma and b cells cancers.

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives