ECTRIMS ACTRIMS 2020 Abstracts Online….This year I’ve been given the Heave-Ho. So you can do it yourself!

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Normally Alison, NDG and DrM&M and I prepare and give a live presentation of the weeks events at ECTRIMS 2020…..but not this year:-(

We have also created and organised the live Burning debates…..but not this year:-(.

We have been given the Heave-Ho…Maybe MS Social Media stars Brandon Bieber and Armish Boster (only joking) from the USA were going to do a Social Media double act before COVID-19 kicked-in.

Is this not Brandon Beaber MD

So you will have to do this yourself

Have a look through to see what you are interested in....

https://cslide.ctimeetingtech.com/msdc2020/attendee/confcal/session

https://cslide.ctimeetingtech.com/msdc2020/attendee/confcal_1/session/

There are a load of COVID-19 presentations including another one saying CD20-depletion increases the risk of COVID-19.

However, you could go to learn about B cells. Here is the abstract of a talk

PS06.02 – Mechanisms of Action of B Cells

B cells play a central role in multiple sclerosis (MS) pathology. B and plasma cells, and their antibody products, are found at elevated levels in MS patient cerebrospinal fluid and demyelinating lesions, and B cell-predominant germinal center-like aggregates are observed in relapsing and secondary progressive patients MS patients. In Phase 3 clinical trials, relapsing MS patients treated with anti-CD20 monoclonal antibodies demonstrate reduced MRI lesion activity, clinical relapses, and disability progression; and early Phase 2 clinical studies of Bruton’s tyrosine kinase inhibitors show reduction in active MRI lesions. B and plasma cells may modulate MS disease activity through multiple mechanisms including antigen presentation, pro- and anti-inflammatory cytokine secretion, and auto-antibody production. Molecular and functional analyses of B cell populations have indicated that B cell subpopulations and mature antibody producing cells (plasmablasts and plasma cells) display complex interactions with other immune cell populations to modulate MS disease activity in the periphery and within the central nervous system. These effects are further modified by secreted immunoglobulins acting independently or in concert with other cellular immune responses. Sophisticated translational investigations and experimental models are primed to expand our understanding of MS B cell pathophysiology and advance the development of new B cell therapeutic

But a talk about B cells and no mention of you know what (the M word)….I wonder what are they going to tell us….CD20T cells are made by B cells (No that’s someone else)?….I think. that I will pass on this and save a few minutes….otherwise I may shout “It’s behind you”. Let’s keep it as our dirty litle secret

If you remember I had a dig at the ozanimod crowd for not mentioning the effect of ozanimod on memory B cells. This published paper is presented here at ECTRIMS 2020

P0325 – Effect of ozanimod on proportions of leukocyte subsets in patients with relapsing multiple sclerosis (ID 979)

In a phase 1, open-label, pharmacokinetic/pharmacodynamic study, 24 participants with RMS were randomized to oral ozanimod 0.46 (n=13) or 0.92 mg/d (n=11) [equivalent to ozanimod HCl 0.5 or 1 mg] for ~12 weeks, including an initial 7-d dose escalation (0.23 mg/d x 4d + 0.46 mg/d x 3d). Exploratory analyses used flow cytometry to characterize proportional changes from baseline in leukocyte subsets on days 28, 56, and 85 in total peripheral blood mononuclear cells (PBMC) and total T cells. Ozanimod was associated with dose-dependent decreases in absolute numbers of CD4+ and CD8+ T cells.

But they must have been listening and did another poster, this time mentioning the Memory B cells

P0228 – Post-treatment recovery of lymphocyte subsets in healthy volunteers treated with ozanimod (ID 861)

Background

Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, was recently approved in the US and EU for the treatment of relapsing forms of MS (RMS). Ozanimod blocks the capacity of lymphocytes to egress from lymphoid tissue, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in MS is unknown but may involve reduction of lymphocyte migration into the central nervous system. In healthy volunteers (HV) and patients with RMS, ozanimod induces differential reductions in lymphocyte subset counts.

Objectives

To evaluate the recovery of lymphocyte subsets to pre-treatment levels following discontinuation of ozanimod in HV.

Methods

In a phase 1, randomized, double-blind, placebo-controlled study (NCT03694119) in HV (25–55 y), oral ozanimod 1.84 mg/d (2 x the approved dose, n=27) was administered for 28 days, which included a 10-day dose escalation (0.23 mg/d x 4 d, 0.46 mg/d x 3 d, and 0.92 mg/d x 3 d). Lymphocyte subset counts were evaluated at baseline and at 7±2 and 75±10 days after cessation of ozanimod. Lymphocyte subsets were measured using an epigenetic platform and are summarized descriptively as mean (standard deviation [SD]) percentage change from baseline.

Results

At 7±2 days after cessation of ozanimod, total lymphocyte counts were reduced by 52.4% (23.0) from baseline and CD3+ T cells were reduced by 49.7% (20.1). Within the T-cell population, CD4+ (−56.1% [22.5]), CD8+ (−39.3% [24.5]), regulatory T cells (−31.6% [30.3]), and Th17 cells (−36.5% [27.2]) were reduced from baseline. Total B cells (−56.3% [25.3]) and memory B cells (−46.6% [16.5]) were also reduced. At 75±10 days after cessation of ozanimod, total lymphocytes and all subsets had recovered to near baseline values, although at different rates. Total lymphocytes (−18.3% [26.1]) had less recovery than CD3+ (−4.8% [28.0]), CD4+ (−14.5% [27.5]), and CD8+ (−11.0% [26.0]) T cells. Th17 cells (3.8% [33.5]) recovered faster than regulatory T cells (−15.4% [28.8]). Total B cells (−18.6% [25.1]) and memory B cells (−18.9% [24.7]) had recovered less than T cells.

Conclusions

Ozanimod induced differential declines in T and B cell subsets in HV. By the final assessment at 65‒85 days after cessation of ozanimod, all cell populations evaluated showed gradual and variable rates of recovery to near baseline levels, indicative of a return of circulating lymphocytes toward pre-treatment levels.

Em ~50% reduction. Therefore it makes me wonder if the clinical effect is as good as the 80% memory B cell depleters?

Importantly it seems ProfG gets his DoDo trial (Double dose of Ocrelizumab) and there is a presentation on the design. P0230 – Rationale and design of two Phase IIIb studies of ocrelizumab at higher than the approved dose in patients with RMS and PPMS. But it seems the manufactures have not had the Jajce to do the ADIOS trial to determine whether anti-CD20 depletion has IRT-like activity  

However I’ll be running to look at this one

P0892 – Ocrelizumab as an immune reconstitution therapy? A case report. (ID 1830) Hrastelj et al.

Background

Ocrelizumab is one of the most effective disease-modifying drugs for MS. As a potent immunosuppressor, ocrelizumab carries significant infection risk and its long-term effects on immunocompetence are not fully understood. Although ocrelizumab is given as a regular six-monthly infusion, it shares several characteristics with immune reconstitution therapies, such as alemtuzumab and cladribine. Alemtuzumab and cladribine deplete circulating lymphocytes and ocrelizumab specifically depletes circulating B-cells, with reconstitution of cells occurring from bone marrow. It is not known whether the therapeutic effect of ocrelizumab outlasts the administration period. Giving ocrelizumab in a time-limited fashion could reduce both short- and long-term side effects, as well as provide a substantial cost reduction.

Objectives Share experience of a case in order to stimulate investigation into ocrelizumab as an immune reconstitution therapy.

Methods

1. Consent was successfully obtained to present the patient’s case.

2. Case details were collated, including radiological and laboratory data.

Results

A 24-year-old female patient was diagnosed with MS following subacute onset left hemiparesis, positive CSF oligoclonal bands, exclusion of mimics and MRI showing multiple T2 lesions in the periventricular areas, corpus callosum and juxtacortical areas. Her baseline MRI performed immediately prior to treatment commencement showed five new T2 lesions with new enhancement. She was treated with five doses of ocrelizumab at six-monthly intervals between 2012-14 as part of a clinical trial. She then decided to withdraw from the study to travel, but returned to the UK in 2020. Despite cessation of all disease modifying treatment for six years the patient reported no clinical relapses, and in comparison with the MRI at treatment cessation in 2014 there were no new lesions or enhancement. Lymphocyte subset analysis showed reconstitution of B-cells (578 x 106 cells/L; normal range 50-500 x 106 cells/L). The patient is fit and well and suffered no side effects of treatment.

Conclusions:

A patient treated early with a limited course of ocrelizumab for two years demonstrated no evidence of disease activity (NEDA2) after six years without treatment. Caution is recommended in extrapolation from a single case, however investigation of ocrelizumab as an immune reconstitution therapy is warranted. Limited duration ocrelizumab treatment could have substantial benefits in terms of side effects, cost and patient convenience whilst maintaining efficacy.

I guess with time the ADIOS study will get done by academic neurologists.

Come on Roche/Sweden/Kaiser/Rituxiland or the NHS….you can do it properly and put this issue to bed…it’s about Patient Safety!

Could they get a patent on the dosing schedule and make the exercise worthwhile?

Also as I said a few days ago on the FLIP FLOP post that once you have sequenced the immune cells the next thing you do and see what the antibodies they make bind to….and the prediction is not myelin but stuff inside cells that are released secondary to damage. We didn’t have to wait too long

PS06.03 – The antigenic repertoire of CSF-derived B cells in early untreated multiple sclerosis.

Background. B cell depleting therapies are highly effective treatments for multiple sclerosis (MS). B cells are more numerous in active than inactive lesions, and their intrathecal clonal expansion and oligoclonal band production are hallmarks of MS. B cells also present antigens to T cells and secrete inflammatory cytokines. The antigenic specificity of individual B cells in cerebrospinal fluid (CSF) obtained from patients with early MS may help further clarify the role of B cells in MS biology.

Objectives: To determine the viral and autoantigen repertoire of CSF-derived, class-switched B cells from untreated, early MS patients.

Methods We performed single cell immunoglobulin sequencing on CSF plasma cells, plasmablasts, and class switched memory B cells from 9 untreated patients: five with relapsing remitting MS (RRMS) and four with clinically isolated syndrome (CIS). The interval between the first attack and lumbar puncture ranged from 1 – 222 days (median 67 days). Brain and spinal cord MRIs performed concurrently with lumbar punctures revealed 5/9 patients with gadolinium enhancing lesions.

Using paired heavy and light chain immunoglobulin sequences, we generated 75 monoclonal antibodies (mAbs) and screened them on a suite of unbiased antigen discovery platforms: 1) mouse brain tissue staining, 2) whole human proteome programmable phage display, 3) pan-viral programmable phage display, 4) mouse and human brain immunoprecipitation mass spectrometry.

Results: The mAbs showed diverse antigen specificities. Candidate antigens were primarily ubiquitously expressed, intracellular proteins; however, a minority were macromolecules associated with the plasma membrane and/or enriched in brain tissue. Shared antigenic targets were occasionally identified within subjects but were rarely identified across subjects, with the latter including cytoskeletal proteins. For two mAbs, high-confidence antigens with prima facie relevance to MS were identified: 1) a white matter-restricted lipid species, and 2) an Epstein-Barr virus-interacting host protein.

Conclusions. Using our panel of 75 mAbs derived from plasma cells, plasmablasts, and class-switched memory B cells found in the CSF of early, untreated RRMS/CIS patients, we identified a diverse repertoire of antigenic targets, with a majority comprised of intracellular host proteins.

There you go not a bad guess….well not really a guess. This approach has been one before and guess what? They found the same thing.…all you have to do is read:-)

About the author

MouseDoctor

14 comments

  • Hi MD,

    This is how I like my science – with a good dose of British humour! Can we mere mortals access the Ectrims talks? The Ocrelizumab one you referred to sounds interesting as does Prof G’s presentation…

    • I dont think mortals can attend due to The Association of the Pharmaceutical Industry rules of not mixing mortals with deity

      • Quite right too. In mythology mortals and Gods mixing has only ever led to chaos.

        I was hoping that some of the talks would be recorded so we could watch them after. It’s a pity that you’ve been axed, I never got to see one of your live presentations and now shall forever wonder if you were like Graham Norton at Eurovision.

        By a stroke of luck though, I may have happened upon a German semi-version of the Barts team and they are giving a couple of talks in October about what they learned from Ectrims. It will be interesting to see how they interpret things and cross-reference it with anything that appears one here.

          • Hi AANON,

            A link for the talks by the German neuros? I’m afraid they’re not online but are taking place at their clinic a couple of weeks after Ectrims.

        • I am hopng the talks will be recorded too…ACTRIMS at saturday night at 10 is no fun, but unless someone coughs up the registration fee i will be buying £250 worth of ice cream instead….I’m hoping someone will lob me their pasword:-). I learned from the European Association of Meurology in July that if the talks are recorded you can fast forward through the 30 min talk and get to the punchline and listen for 30seconds and go to the next talk. 2 hours and the 3 days of meeeting and 2 days of traveling was done…sorted.

          On the other issues the semi-version and humour does not compute:-). I am remardably serious but would love to do the eurovision..then I could understand the Heave Ho however I am sure the past ones are on the web, the best bit was NDG when she thought she was being accused of a liking a swift Sangria and G&T

    • Yes but we have these sessions each year and they are otfen as exciting as the microbiome talks…only joking but they tend to be very sscientific and a long way from the clinic…maybe this year will be different

  • I think you should raise your online profile, become a YouTube influencer. Fashion, makeup, hair and MS. I’d watch and so would my wife.

    I saw a Ectrims poster about a 24 year cladribine retrospective. Any idea what this could be about?

    • 24 years…Probably a lie….oral cladribine has been about since the naughties…as for you tube influencer. NDG has the outfits I have the same SH1 suit (eyp the birthday suit) after all it is Monty Python

  • I believe Genentech started, or will be starting, 1200mg(double) and 1800mg (triple) dose studies, which could give data on DrG’s hypothesis of higher dose deep tissue (peripheral),and the 3 compartments of CNS, penetration Pharmacokinetic data.

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