International ME/CFS Conference 2025 Berlin May 12-13

Discussion in 'ME/CFS research news' started by Jaybee00, Mar 30, 2025.

  1. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    OK. The first slide seems to show an impressive relation between improvement and NK numbers. The suggestion is that daratumumab efficacy is mediated through NK cells and so maybe patients with low NK numbers do not kill enough plasma cells. So the NK number is related to the drug action rather than anything to do with the ME/CFS I think. On its own the slide makes quite a convincing for the clinical action of Dara being real but the numbers are small.

    I would love Oystein to be proved right that cutting antibody is useful. I have an idea that might fit with that but the route back to the original serendipitous observation is getting quite tortuous.

    I also think it is possible that low NK cell numbers and/or function reflect a compensatory rise in TGF beta, which may reflect more severe disease or a different disease. So the NK cells might be a real but epiphenomenal part of the biology.

    They also seem to be showing that NK cells get clobbered a bit by Dara - which is maybe not surprising but probably irrelevant.
     
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  2. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I think 'T cell exhaustion' is a metaphorical term of art rather than meaning literally that cells are exhausted. It is a particular response pattern that someone gave that name. Both of these studies may well be picking up real changes but there is a continuing problem with interpreting peripheral blood cell studies when we may be looking at compensatory effects due to shifts in trafficking. Until recently studies of peripheral blood cells have been very hard to replicate. These authors are careful so maybe we are beginning to see the biology being picked out. I would just be very wary of calling this 'exhaustion'.
     
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  3. rapidboson

    rapidboson Senior Member (Voting Rights)

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    Important to add that he himself showed this data only tentatively. Saying that it might well be chance, but with their small cohort they have seen this correlation. Thus going forward, to more successfully meet endpoints, they will introduce NK cell amount as an inclusion criterion.
     
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  4. V.R.T.

    V.R.T. Senior Member (Voting Rights)

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    Yeah, that's concerning, but it's two patients and the NK business could explain it. We will have to wait and see what happens to severe patients in phase 2 I suppose.
     
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  5. Liie

    Liie Established Member

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    I think this is the same study that was given a short presentation at a conference held by the Swedish ME association (RME) last year:

    https://www.youtube.com/watch?v=nCik6NamXdo




    Annoyingly the forum doesn't seem to allow me to link to a specific time in the video. But the information about the daratumumab study starts at around 12:00.
     
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  6. leokitten

    leokitten Senior Member (Voting Rights)

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  7. Dolphin

    Dolphin Senior Member (Voting Rights)

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  8. V.R.T.

    V.R.T. Senior Member (Voting Rights)

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    In the q and a fluge says that an american company is considering a trial of CAR T therapy for ME/CFS, but he thinks it's too risky at least at present. He says maybe in 5 years...
     
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  9. rapidboson

    rapidboson Senior Member (Voting Rights)

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    But the person asking the question (I believe it was Prof Birgit Sawitzki) said that for autoimmune diseases the side effects are much more benign than with cancer (which is what Fluge was basing his reply on iirc), right?
     
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  10. V.R.T.

    V.R.T. Senior Member (Voting Rights)

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    Possibly stupid question-

    If it does turn out that there is a relationship between NK cells and drug action as opposed to disease process, is there a way to increase NK cell numbers in low NK patients so that when they get dara it kills enough b cells?

    Or would that be impossible/undesirable for other reasons?
     
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  11. V.R.T.

    V.R.T. Senior Member (Voting Rights)

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    Yes that is true, she did say that. I wonder who the company is...
     
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  12. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    The German group are giving the impression that problems with CAR-T for autoimmunity are small but my own information from colleagues now using it at UCL is that they are far from trivial. And we have no idea about long term risks like increased rates of lymphoma or cancer from B cell depletion. The experience with rituximab looks OK as far as I know but you cannot trust drug companies and CAR-T may do something more profound to anti-cancer immunity.
     
  13. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    You could switch to a monoclonal that makes more use of complement than ADCC or shift the dose of Dara. Or use two antibodies, or whatever. Unless NK cells are seriously deficient I suspect there is a way around it. The first thing is to show the drug is useful and the next, more difficult, thing is to get drug companies to make sensible decisions on modifying regimens. They aren't aways co-operative.
     
  14. rapidboson

    rapidboson Senior Member (Voting Rights)

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    I read that isatuximab can induce apoptosis directly apparently?
     
  15. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I think a lot of the antibodies can do all three mechanisms to a degree. Venkat Reddy is the expert on this.
     
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  16. rapidboson

    rapidboson Senior Member (Voting Rights)

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    Thanks for the info! The Prof asking the question made it sound like they've been testing CAR-T cells themselves and have seen much more benign side effects in autoimmune indications. But no idea, just sharing what I heard!
     
  17. rapidboson

    rapidboson Senior Member (Voting Rights)

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    Oh I meant anti CD38 mAbs specifically, from what I can see it's only Dara and Isa, and apparently only Isa can induce apoptosis alone? Idk, just what a quick Wikipedia search said, they referred to a 2019 trial that I didn't read.
     
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  18. leokitten

    leokitten Senior Member (Voting Rights)

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    @Jonathan Edwards you’ve stated repeatedly that RituxME trial results showed that B-cell depletion doesn’t work for ME. Fluge and Mella (and I in previous responses to your comments) disagree they said in their presentation that indeed for a subset it does work. What are your thoughts on this?
     
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  19. arnoble

    arnoble Established Member (Voting Rights)

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    Given LLPCs express CD38 but not CD20, and given LLPCs are largely responsible for sustained antibody production, a non-scientist like me is curious to know why the RituxME study did not try something like Daratumumab instead?
     
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  20. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    If there was no difference from controls in blinded studies then I don't think anyone can claim efficacy in individuals. The blinded phase II study did not convincingly show benefit. There was a statistical difference at a six month endpoint that was not the primary outcome measure. But looking at the pharmacodynamics I think that could easily have been a chance finding. I have not heard claims from Fluge and Mella that it definitely works in individuals. If they are making such claims I don't think I can agree.
     
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