Whilst pharma data analysis says we can’t find anything, a critical eye fingers CD4 T cells as being important in disease break through after alemtuzumab.


Alemtuzumab. The irony of Humanisation. Part V…

David Baker, Liaqat Ali, Gauri Saxena,  Gareth Pryce,  Meleri Jones,  Klaus Schmierer, Gavin Giovannoni, Sharmilee Gnanapavan,  Kathleen C. Munger,  Lawrence Samkoff, Andrew Goodman and  Angray S. Kang. The irony of humanization: Alemtuzumab the first, but one of the most immunogenic, humanized monoclonal antibodies Front. Immunol. doi: 10.3389/fimmu.2020.00124

Seeing the World throw the DrAngry glasses must wait until later, but they are not rose-coloured like ProfG’s

This has been posponed until the manuscript goes online so back on monday to finish it off, but you can read the abstract now. But whilst looking through the new additions in the journal I came upon this one article below

I have been a memory B cell supporter but I keep an open mind and it is likely that B cells help T cells and vice versa. Does this new paper dent the memory B cell idea? On the surface you say yes, but I think no, but it says we need independent assessment to the CARE-MS data.

Event-Driven Immunoprofiling Predicts Return of Disease Activity in Alemtuzumab-Treated Multiple Sclerosis Akgün et al. Front Immunol https://doi.org/10.3389/fimmu.2020.00056

Background: Alemtuzumab is a highly effective drug for the treatment of multiple sclerosis (MS), characterized by specific patterns of depletion and repopulation. As an induction-like treatment concept, two mandatory infusion courses can inhibit long-term disease activity in the majority of patients, and additional courses can successfully manage subsequent re-emergence of disease activity. Currently, there are no biomarkers to identify patients with re-emergent disease activity requiring retreatment.

Methods: In this study, we systematically characterized 16 MS patients commencing alemtuzumab. Clinical parameters, MRI and detailed immunoprofiling were conducted every 3 months for up to 84 months.

Results: Alemtuzumab led to significant decrease in clinical disease activity in all evaluated patients. Nine out of 16 patients presented with no evidence of disease activity (NEDA)-3 up to 84 months (“complete-responder”), while 7 patients demonstrated clinical or/and subclinical MRI disease activity and received alemutzumab retreatment (“partial-responder”). In both response categories, all T- and B-cell subsets were markedly depleted after alemtuzumab therapy. In particular, absolute numbers of Th1 and Th17 cells were markedly decreased and remained stable below baseline levels—this effect was particularly pronounced in complete-responders. While mean cell numbers did not differ significantly between groups, analysis of event-driven immunoprofiling demonstrated that absolute numbers of Th1 and Th17 cells showed a reproducible increase starting 6 months before relapse activity. This change appears to predict emergent disease activity when compared with stable disease.

Conclusion: Studies with larger patient populations are needed to confirm that frequent immunoprofiling may assist in evaluating clinical decision-making of alemtuzumab retreatment.

This study looks at the absolute number of cells after alemtuzumab and shows that in people who are responding well to allemtuzumab the T cells do not reach normal levels for over 7 years, which is not exactly the inference in the European Label that things are back to normal relatively quickly. Both Th1 and Th17 cells were depleted for 7 years. Memory B cells get back to baseline within 2.5 years for the treatment onset and had a bit of an overshoot at year 3-4.

What happened in the people who showed disease breakthrough? On a population based approach you can’t see the wood for the trees just like has been said by the author’s, German Colleagues, who published what looked like a company sponsored paper. This looked at the depletion over a couple of years and then tried to associate it with disease break through over 5 years. They found nothing rather unsurprsingly. Oh well, as we don’t know where to look we maintain the Staus Quo and we can keep flip-flopping.

As you know I never was a Status Quo fan

Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab.Wiendl H, Carraro M, Comi G, Izquierdo G, Kim HJ, Sharrack B, Tornatore C, Daizadeh N, Chung L, Jacobs AK, Hogan RJ, Wychowski LV, Van Wijmeersch B; CARE-MS I, CARE-MS II, and CAMMS03409 Investigators. Neurol Neuroimmunol Neuroinflamm. 2019 ;7(1). pii: e635.

However the Dresden group, here thought that if you look at the data with a critical eye and relate cell repopulation to disease breakthrough, to you may be able to see something.

Analyzing the time period 12 months before the MS relapse in an event-driven manner, CD4+ T cells, CD8+ T cells, CD19+ B cells, as well as naïve and memory T cell subsets and Treg cells, immature B cells and B reg cells, were stable and did not significantly differentiate between good and parial responders.   However, they could demonstrate an absolute increase of Th1 and Th17 cells starting 9 months before relapse and peaking at the relapse itself . They did not see an effect on memory B cells, although they say a small albeit insignificant increase observed in the memory B cell counts starting 6 months before relapse, with highest values at clinical onset of the relapse itself. Clearly that TH1 and TH17 are flatlined for 7 years allows an increase to be seen, which may be masked in part by the natural recovery of memory B cells.

This conclusion has been reported before Clinical relevance of differential lymphocyte recovery after alemtuzumab therapy for multiple sclerosis. Cossburn MD, Harding K, Ingram G, El-Shanawany T, Heaps A, Pickersgill TP, Jolles S, Robertson NP. Neurology. 2013;80(1):55-61. This view was quickly put down by Cambridge using their data, but perhaps an independent look at the CARE-MS data with the same critical eye should be able to confirm or refute the data from the 16 people looked at here.

They (Weindl et al) have made “data availablity for CARE-MS” statement in the paper by Weindle, time to get independent analysis of depletion and anti-drug antibody data.

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  • You’ve worked hard MD, but I wonder what will be the benefits to new RRMS patients? Is there something practical that will flow from this work?

    Also, Cambridge we’re doing the original trials of Campath in the early 1990s – some 30 years ago. This is an old drug and the game should have moved on in this time frame (would you be happy using a Sinclair zx81 in 2020? ). Trawling through the data of old trials can provide many insights (and keep researchers busy), but I’d rather the researchers involved in this paper would focus on the future – new therapies to deal with progression, smouldering MS and neuro-protection. There are 130000 people with MS in the U.K. and most will have had the disease for 10+ years and Lemtrada will not be an option.

    So well done Mouse and co, but you now need to shift from being Time Team (digging through the past) to shifting the focus to future therapies which address the real MS (not just focal inflammation).

    • Is there something practical…..
      (1) Next generation of more selective treatments with reduced side effects.
      (2) Knowing where to look so you focus on the right thing to understand the right biology
      (3) Safer use of existing treatments

      This is an old drug, but if you read the blog you must realise that there is no quick path to change. If I have a cure in my hand now, it will take 10-15 years for this to be a treatment, if I am a pharmaceutical company and if not much longer. So would I be happy on a Sinclair C5…no they seemed like death traps (coffin on wheeels) and they looked really SH1 and I wouldn’t be seen dead in one, but if that is what is available verses shanks’ pony (https://en.wiktionary.org/wiki/shanks%27_pon) then I may consider it. Some may say the same thing about using a Smegway or hydroscooter…modern technolgy but a choice whether to use it or the old technology (car), many still like the old tools because they are better.

      I would rather the “researchers focus on the future”…First this paper is not us, so they (Dresden group) have to defend their actions not me, but if you are shooting the messenger then it doesn’t have to be an…either…or. A lot of our energy is focused on smouldering MS and has been for many years, but much of it is not ready for prime time and so we don’t take about it.

      Again new therapies take time, it has only been 19 years for one of the current ones we have been working on and you have no idea what it is because we han’t been taking about it….will this approach target smoldering MS…maybe.

      You say Lemtrada will not be an option for many….. however, it was indeed available to many until Novemeber 2019, when the European label was changed. Up to then it had the most liberal licence of any European drug (one MRI lesion etc). It was not used as much as it could have been that is not my choice or capacity to influence. The work presented today was finished 3-12 months ago at least.

      As for being Time team…I think the people getting the test as a result of our digging and sifting and avoiding the issues of not being effectively treated would be grateful. What I have described this week so far, is bigger than alemtuzumab and bigger than MS. Alemtuzmab has provided a story but if being used in haemophilia, and a number of other autoimmune conditions. However whilst researching old stuff, we have uncovered an example of £85,000-£100,000 worth of futility, 4 clinical episodes and 3 points on the EDSS scale, would you want to be that person. This should never happen again.

      As for the “real MS”… you must have been reading too much Peter Stys, it is not “Will the real MS stand-up”, but will the academic community do some reading and thinking and learn from the biolgy and the clinical reality. We were working on smoldering MS years before someone thought about that catch phrase and as for real MS, it is probably just a part of MS, made up by someone looking at something that wasn’t MS (I’m told it was NMO).

      • “Again new therapies take time, it has only been 19 years for one of the current ones we have been working on and you have no idea what it is because we han’t been taking about it….will this approach target smoldering MS…maybe.”

        But is this therapy you have been working on in human trials or still in the navel gazing stage?

        Out of interest “The Empire State Building took only one year and 45 days to build”.

        On the assumption that you have 2 beers a day on average, you have consumed nearly 14000 pints since the work on this mystery therapy.

        2001 – Shrek was released.

        2001 – Tony Blair was in his 4th year as PM

        2001 – Can we fix it? by Bob the Builder got to number 1.

        How can anything take 19 years and still not be delivered! What do you say in your annual appraisal? I’ve made some progress this year but will need a couple more decades! If I was your boss (or the boss of Team G) I’d say “pull your socks up, get a move-on, if this isn’t sorted in the next 12 months you’ll be getting your P45”.

        I’m going for an afternoon nap as this has made me so angry.

        • How can anything take 19 years and not be delivered?….Whilst you may be angry, without meaning to be rude I am sorry to say you have no real appreciation of what it really takes to try and delivery treatments from scratch if a pharmaceutical company is not involved. Yes humans have been involved in our studies, but I am sure you will tell me next that I am so fat and Lazy that I can’t even see my navel to gaze at:-). If you have deep pockets or a benefactor you can push things abit, but JKR for example has gone elsewhere:-(, but without big pharma you could spend a lifetime and you may not make it and for many they do not even try and stay in Scienceland forever. Their head never goes above the parapet

          But again shooting the messanger, gets us all nowhere. Only it gives one a headache and a need to lie down. We do put our heads above the parapet and people like to take a pop, but do we have to be punching bags?. However, for the resource we have recieved I think TeamG can rub shoulders or stand on the shoulders of many academic groups. We do not simply work on one thing as that would be scientific suicide when you go down a blind alley and yes we do have annual appraisals. We have contributed to a number of developments that have benefited people with MS, in many ways that you do not, and will, not know. You are not alone in your view about what we have or haven’t done….maybe you are referee #1, if you are ProfG may have a few things to say to you.

          As for being fixated with 2001, we defining the endocannabinoid system as a target for MS, in 2019 Sativex became available via NHS England supported by our work reported in 2000, but done in 1998, So 23 years for that one. It was about the time we stopped curing autoimmunity in mice. Dammed if you do, dammed if you don’t

      • I would love a test to work out whether a treatment is working. Taking a drug and hoping for the best, only to find it is ineffective is utterly disheartening – and I feel I hardly need to mention the effect on disability and all that brings to the party…

  • Other find a similar increase in non responders for the cd4 t cells

    “DISCUSSION This study of a well-defined cohort of
    alemtuzumab-treated patients with MS confirms differential
    recovery of lymphocyte subsets7 and supports the
    hypothesis that variation in lymphocyte recovery following
    treatment is clinically relevant. In this group, accelerated
    CD41 recovery was associated with early return
    of disease activity, suggesting that CD41countsmay act
    as a surrogate marker for treatment response and indicating
    the necessity for personalized treatment protocols”

    Clinical relevance of differential
    lymphocyte recovery after alemtuzumab
    therapy for multiple sclerosis


    Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia
    especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients
    with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased
    and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just
    mildly affected and was slightly below the lowest normal limit already before alemtuzumab. These cases anticipate
    further studies aimed to investigate whether the evaluation of the CD4+cell percentage could represent
    a helpful tool to address the individual clinical response to alemtuzumab.

    Lack of CD4+ T cell percent decrease in alemtuzumab-treated multiple
    sclerosis patients with persistent relapses


    Also it seem that t cell (and b )get reduced for much longer ( in RA treated patients 20 years)

    Immune reconstitution 20 years after
    treatment with alemtuzumab in a
    rheumatoid arthritis cohort: implications for
    lymphocyte depleting therapies

    It disease specific?

    • Thanks for this I had missed the case report by Rolla et al. 2017. Patient #1 and Patient #2 looks like classical neutraliser and failer as they respond to first dose and not to the second or subsequent doses. If they had looked at CD8 they would have seen the same thing as you can see the lymphocytes dont deplete. However in the discussion antibody neutralization was not mentioned. That is why our studies are important. They got 3 doses that did not work and had disease breakthrough.

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