Invest in ME Conference 12: First Class in Every Way
OverTheHills wraps up our series of articles on this year's 12th Invest in ME International Conference (IIMEC12) in London with some reflections on her experience as a patient attending the conference for the first time.
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Anti-CD20 trial for Intra thecal Rituximab started whilst another stopped for lack of efficacy Toda

Discussion in 'Rituximab: News and Research' started by Ecoclimber, Feb 20, 2016.

  1. Ecoclimber

    Ecoclimber Senior Member

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    Premission to repost by Prof. Gavin Giovannoni

    There are some in the ME/CFS medical field that believe ME/CFS is 'MS Light' or 'Atypical MS'. The reason I post these articles is the fact that research in one area may spill over into another area of research or the fact that researchers reviewing a site may look at the research in another disease category that could be related to theirs and it might raise their interest level.

    Futhermore, research may be further ahead in another field that ME/CFS researchers wish to explore if they had the funding and the researchers to explore such as EBV, HERVs, Autoimmune diseases, Fibromyalgia, Lyme etc.


    @Jonathan Edwards I find this interesting as it relates to Riuximab for being underpowered to stop PPMS as for the inability to deplete B-cells in CNS

    Anti-CD20 trial for Intra thecal Rituximab started whilst another stopped for lack of efficacy


    Today we have a B cell flavoured day at ACTRIMS as CD20 depletion is at the forefront

    If one person has an idea another is having it at the same time.


    Leptomeningeal inflammation and Intrathecal Rituximab in Progressive MS
    Dr. Peter A Calabresi, MD, Johns Hopkins University, Baltimore, MD

    While many treatment options exist for the relapsing form of MS, there are no effective therapies for progressive MS. Pathological studies have shown the presence of leptomeningeal inflammation (LMI) in people with MS and it is more prevalent in primary and secondary progressive MS. LMI is linked to increased gray matter demyelination and increased sub-pial lesion load, suggesting a possible role for LMI in disease progression. Identifying this process in vivo has been a challenge, but recent studies have shown that time-delayed post-contrast FLAIR sequences can demonstrate leptomeningeal lesions that correspond to areas of inflammation with lymphocyte aggregates seen on autopsy. These lesions appear to remain stable over time and are seen more frequently in people with progressive MS.

    Our data suggest that in the late stages of the relapsing remitting experimental autoimmune encephalitis (EAE) model in SJL mice, contrast-enhancing lesions emerge in the meninges overlying the cerebral cortex. These lesions persist over time and consist of B and T lymphocytes, suggesting a process that may be similar to LMI seen in people with MS, which could facilitate screening of therapies designed to target this type of inflammation.

    Since anti-CD20 is already FDA approved and has been given intrathecally (IT) to people with MS, we have commenced a clinical trial of IT Rituximab in people with progressive MS who have two baseline MRIs demonstrating leptomeningeal enhancement (LME). Since LME is a persistent process for years, unlike white matter enhancing lesions, any reduction of LME on MRI would be meaningful. The design of the clinical trial and enrollment to date will be discussed.

    But as a trial starts another is stopped prematurely because it isn't going to work

    Intrathecal Rituximab in progressive MS stopped for insufficient inhibition of CNS inflammation: a randomized, double-blind, placebo-controlled studyDr. Mika Komori, MD, PhD, Dr. YenChih Lin, PhD, Dr. Irene Cortese, MD, Mr. Andrew Blake, Ms. Joan Ohayon, CNRP, Ms. Jamie Cherup, RN MSN CRNP, Dr. Dragan Maric, PhD, Dr. Peter Kosa, PhD, Dr. Tianxia Wu, PhD and Dr. Bibiana Bielekova, MD, National Institutes of Health, Bethesda, MD

    Background:

    The lack of efficacy of immunomodulatory treatments in progressive multiple sclerosis (MS) may be caused by the unreachable compartmentalized inflammation in the central nervous system (CNS).
    Objectives:
    The double blind combination of Rituximab by IntraVenous and IntraThecal injection versus placebo in patients with Low-Inflammatory Secondary progressive MS (RIVITALISE; NCT01212094) trial was designed to answer: 1. Whether an induction dose of intravenous and intrathecal rituximab efficiently depletes CNS B cells? and 2. If so, whether this leads to global inhibition of CNS inflammation and slowing of CNS tissue destruction?
    Methods:
    Patients aged 18-65 years were randomly assigned (2:1; randomization sequence table balanced for age) to rituximab (n=18) or placebo (n=9). Protocol-stipulated interim analysis of serum and cerebrospinal fluid (CSF) biomarkers in patients who completed the induction dose of study drug quantified the efficacy of B cell depletion.
    Results:
    The selected rituximab regimen failed to reach criteria for continuation of the trial. Changes in B cell-related CSF biomarkers (soluble CD21 [sCD21] and B-cell activating factor [BAFF]) occurred only in the active-treatment arm. While the mobile pool of CSF B cells was depleted by a median of -79.71% (p= 0.0176), B cells in CNS tissue were depleted inadequately (~-10-20%, p<0ยท0001). Consequently, the T cell specific CSF biomarker sCD27 also decreased only slightly (-10.97 %, p=0.0005), while a marker of axonal damage, neurofilament light chain did not change. Insufficient saturation of CD20, lack of lytic complement and paucity of cytotoxic CD56dim NK cells contribute to decreased efficacy of rituximab in the CNS.
    Conclusion:
    Biomarker studies reliably quantified complementary pharmacodynamic effects of rituximab in the CNS, exposed causes for poor efficacy and determined that the RIVITALISE trial would be underpowered to reliably measure efficacy on clinical outcomes.


    COMMENTS:
    In other trials of intrathecal rituximab it shows that most of the antibody put in the CSF ends up in the blood and it depletes the B cell pool in blood. However eliminating B cells from the CNS is not achieved



    Is the intial trial doomed even before it starts?


    Again 3-4 underpowered studies verses a joined-up definative answer...same old same old:-(


    If you are going for this approach would it not be best to target the Plamsa cells which do not express CD20, ensuring that the antibody is complement fixating and that complement s around and not killing by Antibody-dependent cellular cytotoxicity that need other cells to do the killing

    Reactions:
    Posted by MouseDoctor at 07:00 [​IMG]
    7 comments:

    1. [​IMG]
      AnonymousFriday, February 19, 2016 11:17:00 am
      What is the evidence that B-cells in the CNS is driving the progressive phase of the disease?

      It seems maybe this is not the culprit, so even if you could eliminate oligoclonal bands in progressive disease (not likely with any therapy) it seems maybe this is not the problem in this stage of the disease.
      Reply
      Replies
        • [​IMG]
          AnonymousFriday, February 19, 2016 12:17:00 pm
          Just read the first abstract and nowhere does it indicate B-cell dysfunction is the driver of progressive disease.

          "Profound microglial activation and reduction in neuronal density was observed in both the lesions and normal appearing grey matter compared with control cortex."

          I think if I took the time to read your other links I will come to the same conclusion.
        • [​IMG]
          AnonymousFriday, February 19, 2016 12:42:00 pm
          I guess the question is if you eliminate all of the b-cells (plasma cells) from the CNS, will this stop the progressive phase of the disease. If these B-cells are responsible for generating oligoclonal bands, if you can delete them this would stop progression.

          But from what I have gathered, the progressive phase is driven by chronic activation of the innate immune system such as microglial.
        • [​IMG]
          MouseDoctor2Friday, February 19, 2016 12:47:00 pm
          That indeed is the question, which needs addressing. You're right that the progressive phase involves activated microglial cells which also have Fc receptors which detect immunoglobulin and stimulate phagocytosis. So the presence of immunoglobulin from long-lived plasma cells in the CSF could be a driver of progression.
        Reply
    2. [​IMG]
      MouseDoctorFriday, February 19, 2016 1:03:00 pm
      I believe that you are right and the b cell and progression is part of a red herring. It is a hypothesis that b cells drive progression. There is no question of lesions on the surface of the brain and it is clear that antibodies in CSF can be damaging. The b cell follicles are debatable but people with Ms have oligoclonal b cell activation. Get rid of them and if MS goes away then QED. Likewise target innate inflammation and progression stops QED. However go about it half cocked and you end up with cock-up. Rituximab is never going to get at the plasma cells so it won't answer the question. 5 min of thought process rather than suck it and see. sometimes that works but generally it doesn't. Just because you can doesn't mean you should and if it puts the cause backwards then it is bad news.
      However Tally Ho is the clinical mantra maybe it is better to try and fail than not to try at all.
     
    Marco likes this.
  2. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I have two thoughts about this.

    Firstly we know that there are likely to be problems trying to kill B cells in brain through the CSF route. Rituximab needs to kill either through complement, ADCC or apoptosis. Apoptosis may be a weak route. Complement is not much available in CSF and nor are cytotoxic cells to do the ADCC. So it would be an uphill struggle to kill B cells this way. However, B cell survival in CNS will be dependent on a different repertoire of signals from other tissues and it is conceivable that an antibody that is good at inducing apoptosis would work well. There is also a penetration issue. B cells deep in brain may well not be accessed via CSF. CSF is probably the way out for proteins in the brain, not the way in.

    Secondly, treating B cell driven disease, which I think RRMS almost certainly is, but am less clear about PPMS, needs very careful thinking about compartments and cell life histories. Killing plasma cells may be necessary but these may not live that long in brain. That may be why in RRMS attacks only last actively for a few weeks. I would worry that in the abandoned trial result were collected too early. If I was treating PPMS with rituximab I would give it intravenously to wipe out any fresh supply of B cells for 2-5 years (using 6 monthly re-dosing) and then add intrathecal rituximab as a one off and look for benefit from the combined approach at about one year. I might think of mixing it with anti-CD52 (Campath-1H) to remove T cells that might be perpetuating inflammation or maybe an antibody to leucocytes that also picked up plasma cells (not sure if this is a real option - I forget whether they have CD45 for instance). The other interesting thing is that one might achieve lytic levels of anti-CD38 in CSF without risking damage to cells in other tissues that carry CD38 - which has been a problem for IV usage. But this would be a high risk strategy.

    The real problem I see here is in the comments. Neurologists are still very resistant to thikning of MS as a B cell disease. For this reason they are probably not thinking logically about attacking it from all sides in the context of B cell life history (including plasma cell). In oncology it is standard to hit your target from every angle until it just gives up trying to evade you. A similarly aggressive approach is justified in PPMS because it is such an awful illness - far worse than most cancer.
     
    morse27, funkyqueen and Snow Leopard like this.
  3. funkyqueen

    funkyqueen Senior Member

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    South of France
    I asked some MS sufferers ( i do not know the form of their MS), who were having Rituximab, what kind of improvements they had, because i was curious to compare with my results/ with Rituximab results on PwMEers...They were only 9 answerers, but all answered that Ritux litteraly stopped the progression of their MS.
     

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