Getting rid of autoimmunity caused by alemtzumab

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Whac-A-Mole': Why we're losing the fight against organised crime ...

Alemtuzumab is one of the most effective disease modifying treatments, but the major problem associated with it’s use is the development of secondary autoimmunities. What is the problem?

  • One suggestion was that it depends on how T cells repopulate from the thymus.
  • However, we suggested that it could be due to uncontrolled B cell hyper-proliferation in the relative absence of T cell regulation.

Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K.JAMA Neurol. 2017 Aug 1;74(8):961-969.

This idea had been suggested before by a Mexican Lab, but it was ignored and refuted based on the idea that T regulatory cells increase after treatment. However, as we showed that science was flawed and regulatory cells are in fact depleted in absolute numbers. Therefore, there are less T regs to control the rapidly expanding immature B cells.

You may be surprised to know that ProfG and I travelled to Boston about 6-7 years ago to pitch the idea of doing a trial with anti-CD20 to deplete the B cells after alemtzumab.

However, we were before our time and the powers that be were not sufficiently interested in doing the study. Alemtuzumab had no competition at the time as ocrelizumab had not been approved. Remember, rule number 1 of Pharma club is “Do not bring attention to a problem” and rule #2 of Pharma club is “Do not bring attention to a problem”

Importantly it was suggested that we were seeing the hyper-populating B cell response in 1-3 months from treatment, but autoimmunity occurred 12-36 months after infusion. Therefore, how could that be a problem? However, we suggested the autoimmunity was caused early as B cell hyper-populate but do not develop autoimmunity until T cell help appeared and this would take on average over 2 years.

This would say to get rid of autoimmunity, treat shortly after alemtuzumab infusion, if I and ProfG were correct or wait a few years to treat for years as an alternative view if the others were correct.

We are therefore happy that Prof Steinman got off his bum and tested this idea and waited for the B cells to recover and then the team would bash them with rituximab to induce a transient depletion to keep the numbers low such that B cells recover in an environment when T cells are regulated. In this study, there was no autoimmunity during the observation period.

Did our ideas spawn the study, as they were submitted over 4 years ago…. we certainly weren’t credited with this view in the paper, maybe they started before they saw our work..Yes I am sure that’s it……..Yes let’s give them the benefit of the doubt and the credit. Ideas are ten a penny, but it is doing the work that is important.

You stand of the shoulders of what came before…that’s called learning and progress 🙂

Mitigating alemtuzumab-associated autoimmunity in MS A “whack-a-mole” B-cell depletion strategy Ethan Meltzer, Sarah Campbell, Benjamin Ehrenfeld, Roberto A. Cruz, Lawrence Steinman, Matthew S. Parsons, Scott S. Zamvil, Elliot M. Frohman, Teresa C. August 07, 2020 Neurology Neuroinflammation, Neuroimmunology.

DOI: https://doi.org/10.1212/NXI.0000000000000868 

Objective To determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19+ B cells approximates 40%–50% of baseline levels as measured before alemtuzumab treatment inception), can mitigate alemtuzumab-associated secondary autoimmunity.

Methods In this hypothesis-driven pilot study, 10 patients received low-dose rituximab (50–150 mg/m2), a chimeric anti-CD20 monoclonal antibody, after either their first or second cycles of alemtuzumab. These patients were then routinely assessed for the development of autoimmune disorders and safety signals related to the use of dual monoclonal antibody therapy.

Results Five patients received at least 1 IV infusion of low-dose rituximab, following alemtuzumab therapy, with a mean follow-up of 41 months. None of the 5 patients developed secondary autoimmune disorders. An additional 5 patients with follow-up over less than 24 months received at least 1 infusion of low-dose rituximab treatment following alemtuzumab treatment. No secondary autoimmune diseases were observed.

Conclusions An anti-CD20 “whack-a-mole” B-cell depletion strategy may serve to mitigate alemtuzumab-associated secondary autoimmunity in MS by reducing the imbalance in B- and T-cell regulatory networks during immune reconstitution. We believe that these observations warrant further investigation.

Was your career like 'Whack-a-Mole'? – After the Mothership

Whack a mole means smash a mole over the head with a hammer to squash it when it reaches the surface to keep the moles under ground.

Will this give alemtuzumab a new lease of life, maybe but I fear it has collected too much baggage. Will other neuros follow suite and do the rituximab depletion?

Time will tell

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MouseDoctor

22 comments

  • Thank you for all the research in order to improve treatments for pwMS !!🙏🙏🙏
    Great article, I received second round of Alemtuzumab last February.
    What level of B cell should be considered to start low dose rituximab (or other B cell depleter) ?
    My total lymphocyte count 12 months after R1 was 460 (Cd4- 22%, Cd8 – 18%), last blood test (30-07-2020) I had 270/ul total lymphocyte count, if this number stays low there is no need to further depletion, right?
    Thanks in advance

      • “..Yes let’s give them the benefit of the doubt and the credit. Ideas are ten a penny, but it is doing the work that is important”

        Ideas are like rabbits..unless you jump on them and wrestle them to the ground..they hop away.

      • ‘Secondary autoimmunity’ ?
        This presumes the existence of a ‘primary’ autoimmune condition in pwMS which is not susceptible to immune induction as a complication of Alem treatment.
        Would cancer patients treated with Alem and developing eg thyroid autoimmunity have, of necessity, an autoimmune diathesis?
        I asked this question of the Cambridge Alem team some years ago, but didn’t get a credible answer.
        The inflammatory mechanisms in the CNS in MS are damaging but do not necessarily depend on a specific ‘autoimmune’ target?

        • MS is the primary Autoimmunity…the secondary autoimmunities are the B and T cell problems that occur in about 50% of people within 5 years

          The problem with your arguement is the basic details are missing. People with cancer do not get the autoimmune sequalae….

          Look at the list of adverse events of mAbcampath ” The most frequent side effects with MabCampath are: infusion reactions (fever, chills, low blood pressure, itching, feeling sick, hives, increased heart rate, breathlessness), low counts of blood cells (white blood cells, platelets and red blood cells), infections (signs of cytomegalovirus in the blood, cytomegalovirus infection or other infections), gastrointestinal symptoms (feeling sick, vomiting,abdominal pain) and neurological symptoms (insomnia, anxiety). The most frequent serious adverse reactions are low counts of blood cells, infusion reactions, and infections or immunosuppression(reduced activity of the immune system). For the full list of all side effects reported with MabCampath, see the package leaflet.” SEE NO MENTION OF THYROID PROBLEMS

          Therefore (a) People with MS are genetically prone to autoimmunity that is more common than occuring in people treated for cancer. Do the autoimmunities occurin arthritis? I dont know. However the dose and duration of the dose is massively different. MS dose 36mg-50mg in a week. Cancer 90mg a week for 12 weeks. Therefore, the B cell over shoot is going to get “Wack-a-Moled” repeatedly for 12 weeks and this will destroy emerging auto-reactive B cells. Why not use the cancer dose in MS (a) It is not longer available to buy (b) It increaeses risks of infection and importantly (c) Importantly the dosing schedule is not patent protected. This dosing regime filed in about 2006/7 is what allowed MAbCAMPATH to be repurposed to Lemtrada.

          As we wrote previously in the Irony of alemtuzumab…they created the perfect storm of anti-drug antibodies and secondary autoimmunity.
          Maybe if they gave another dose a month after the first it would reduce the autoimmune problems but because of the anti-drug antibody responses the recipients would all (60-85%) be having anaphylactoid like responses.

          • Yes but I dont get your point in relation to side-effects of alemtuzumab…..MS is not autoimmunity to myelin basic protein and to clarify my point further it may not be that people with MS are programmed to autoimmunity, it could be programmed to immunity…i’e’ they give a good response to infections

  • What do you think about pre-dosing with an Anti-CD20 to avoid/decrease IRR? In my view pre-dosing gets rid of b cells so they cannot make anti drug antibodies when alemtuzumab is administered. Does it make sense?

  • MD, about being programmed for good immune response when having MS, I can tell that in the past 12 years, since CIS, I have never got something similar to a fully symptomatic VIRAL infection. Never got the seasonal flu with full symptoms in 12 years, when I had symptoms they were gone in less than 2 days. People that stayed close to me when I had those minor symptoms needed to take a week off work to recover from the flu. I had only one bacterial and one micotic infections.

    I heard of other pwMS being very resistant to infections and turning susceptible after starting DMTs mainly high efficacy.

    If you didn’t already do you could launch a survey on the blog and we will see what is the situation of pwMS 🙂

  • Well this knocks Alem off my alternate DMT list 🙁

    I had an “allergic” reaction to a anti-CD20, so if the only real way to de-risk Alem is with an anti-CD20, pwms like me would not be able to use this approach.

    Maybe if my current IRT approach fails, I will become a “clad lad”.

  • Do the autoimmunities occurin arthritis? I dont know

    “and case note review) focused on new medical diagnoses,
    particularly malignancy, episodes of severe infection
    and autoimmunity. Two patients had a new diagnosis of
    malignancy, both of which were skin cancers with a
    background of Bowen’s disease. Two had new autoimmune
    conditions – hyperthyroidism and coeliac disease.
    The remaining new diagnoses were osteoporosis,
    osteoarthritis, vitamin D deficiency, cardiac arrhythmia
    and ischaemic heart disease. There were no reports of
    severe infection.”

    Yep now you know 🙂

    However

    Discussion:

    We documented two new cases of autoimmunity
    (hyperthyroidism and coeliac disease) but secondary
    autoimmunity has been much less common in RA recipients
    of alemtuzumab than in multiple sclerosis (MS) cohorts.
    In the latter, autoimmunity affected approximately
    one third of alemtuzumab recipients and peaked after
    2 years. It is mainly, but not exclusively, thyroid in nature
    and has been linked to tolerance breakdown during the
    homeostatic proliferation component of immune
    reconstitution [10]. Additionally a recent retrospective
    study of alemtuzumab use in Bechet’s disease demonstrated
    that approximately two thirds of patients achieved
    lymphocyte recovery by a median of 9 months, but 25% of
    patients developed secondary autoimmune thyroid disease
    [11]. Whilst patients affected by these diseases clearly inherit
    distinct genetic backgrounds [12], our data

    demonstrate that patients with RA reconstitute more
    slowly than their counterparts with MS or indeed Bechet’s,
    which may reduce the incidence of secondary
    autoimmunity

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

    https://pubmed.ncbi.nlm.nih.gov/27993172/

    Sharing is caring

    🙂

  • Could rituximab be given at any point after the last alemtuzumab infusion to prevent any secondary auto immunities developing?

    • I suspect not. I think the autoimmunity may develop soon after infusion when there is an imbalance in regulation however there must be enough alemtuzumabers ho have switched to ocrelizumb…Does autoimmunity develop after the switch?

  • UPDATE It seems I have touched a nerve and to get it from the horse’s mouth or in this case the Neuro’s mouth in response to “they started before they saw our work..Yes I am sure that’s it”

    The authors say they stared doing this work in 2014 and discussed it before the trials had finished

    So the idea was spawned in Texas my wrists have been smacked, but as I said ideas are ten a penny and ProfG was talking about the B cell ideas overshoot for many years before we published on it, certainly long before 2014…..the Thompson paper (J Clin Immunol. doi: 10.1007/s10875-009-9327-3) was published in 2010:-). The key is to enact on the question. How long do you have to whack your mole

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