The far reaching arm of alemtuzumab

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Adaptive Immunity Markers- T cells, CD4 and CD8 T helper, B cell subsets,  follicular and splenic marginal zone, B1 cells: Novus Biologicals
The immune system (image from Novus Biologicals)

Whilst we talk about targeted B cell treatments, alemtuzumab possibly is what I’d term a ‘Domestos’ style drug. This type of drug is useful when your aim is to control the entire immune system quickly. Drugs similar to this are cyclophosphamide, cysclosporin and mitoxantrone; which are all considered highly active therapies.

Many of you know alemtuzumab as an anti-CD52. CD52 is found on the surface of mature T- and B-cells, circulating monocytes, macrophages and circulating dendritic cells. So giving an anti-CD52 has an effect on all of these cell types. The effect on the T- and B-cells is quick, with counts dropping to almost undetectable by day 7 by a process of celluar lysis. Following this there seems to be a relative increase in the anti-inflammatory regulatory T-cell pool. These T cells are purported to be the reason for the long-lasting effect of the drug on MS (with most individuals not requiring re-treatment for 4 years).

But, a recently published piece of research also shows that alemtuzumab has off shoot effects on the macrophage pool. This is because the immune system cross-talks. Treating with alemtuzumab appears to promote differentiation of monocytes into anti-inflammatory M2 macrophages, which in turn enhances the regulatory T-cell population. The two then sit in a positive feedback loop promoting the differentiation of each.

Macrophage polarization and specific functions of M1 and M2... | Download  Scientific Diagram
Figure: Macrophage polarization into M1/M2 macrophages (from Phytochemicals as modulators of M1-M2 macrophages in inflammation Apr 2018)

For those who have already benefited from alemtuzumab treatment, this research is a helpful addition. It also points to why certain treatments only need to be used as induction treatments with a few infusions rather than as maintenance treatment with regular treatment.

Abstract

Immunol Cell Biol 2020 Dec 11. doi: 10.1111/imcb.12431. Online ahead of print.

Alemtuzumab mediates the CD 39+ T-regulatory response via CD23 + macrophages

Lital Remez Esther Ganelin CohenDina Safina Mark A Hellmann Itay Lotan Noam Bosak Chen Buxbaum Adi Vaknin Alla ShifrinAyal Rozenberg

Alemtuzumab (ALM) effectively prevents multiple sclerosis (MS) relapses. It causes lymphocytic depletion with the subsequent enhancement of T-regulatory cell population. Direct administration of ALM to T-cells causes cytolysis. However, the T-cells may be indirectly affected by monocyte derived cells, which are resistant to ALM cytotoxicity. We aimed to examine whether ALM modulates monocytes and whether the crosstalk between monocytes and lymphocytes previously exposed to ALM would result in anti-inflammatory effects. CD14+ monocytes of 10 healthy controls and 10 MS (treatment naïve) patients were isolated from peripheral blood mononuclear cells (PBMCs), exposed to ALM, reintroduced to PBMCs depleted from CD14+ cells and then the macrophage profile was taken and T-cells markers were measured. ALM promoted M2 anti-inflammatory phenotype as noted by an increased percentage in the populations of CD23+ , CD83+ and CD163+ cells. CD23+ cells were the highest up regulated (7-fold, P = 0.0002). The observed effect was higher in MS patients as compared with healthy subjects. The ALM- exposed macrophages increased the proportion of T-regulatory cells, without affecting the proportion of T-effector cells. Neutralizing the CD23+ monocyte cells with antibodies reversed the effect specifically on the CD4+ CD39+ T-regulatory cell subpopulation but not on the CD4+ CD25hi CD127lo FOXP3+ subpopulation. ALM induces monocytes’ conversion into anti-inflammatory macrophages, which in turn promote T-regulatory enhancement, in a CD23+ dependent manner. These findings suggest the mechanism of action of ALM is relevant to aspects of MS pathogenesis.

About the author

Neuro Doc Gnanapavan

28 comments

  • Morning,

    I have a question on alemtuzumab that often get asked on this blog in different ways but is yet to be answered. Clearly, it is at its most effective when used early in the disease course. However, at what point is it considered too late? i know that there is not a definitive answer to this question as it will depend on each patients personal circumstances (damage!) but some guiding principles would be gratefully received. A lot of patients, me included, are using this blog to inform their treatment decisions so this is an important issue in my view

    Thank you

    • The phase III trial may have the answer alemtuzumab first (CARE-MS I) , beta interferon first for two years then alemetuzumab (CARE-MS-II), beta interferon for 2, then two years on beta interferon, two years on beta interferon and then alemtuzumab (CARE-MS-II) and look for progression. Where is the paper

      • Thanks MD. I am no scientist so please forgive my naivety as i am learning on the job (an MS patient really is the worst job!). My reading of the results is that the ARR is clearly better in CARE MS 1, as is the NEDA ratio. However BVL is actually better in CARE MS II. If the patients in CARE MS II. What i am taking from this is yes, the earlier the better. However, a couple of years later and the results are still impressive in the BVL stakes. 50% (roughly) didnt acheive NEDA so presumably will still need to undergo another form of treatment in the future? I do not quite understand how the NEDA proportion can go up, surely, it can only come down? Please pour scorn on my conclusions 🙂

        CARE MS I – Most alemtuzumab-treated patients (95.1%) completing CARE-MS I enrolled in the extension; 68.5% received no additional alemtuzumab treatment. ARR remained low in years 3, 4, and 5 (0.19, 0.14, and 0.15). Over years 0–5, 79.7% were free of 6-month CDW; 33.4% achieved 6-month CDI. Most patients (61.7%, 60.2%, and 62.4%) had NEDA in years 3, 4, and 5. Median yearly BVL improved over years 2–4, remaining low in year 5 (years 1–5: −0.59%, −0.25%, −0.19%, −0.15%, and −0.20%). Exposure-adjusted incidence rates of most AEs declined in the extension relative to the core study. Thyroid disorder incidences peaked at year 3 and subsequently declined.

        CARE MS II – Most alemtuzumab-treated patients (92.9%) who completed CARE-MS II entered the extension; 59.8% received no alemtuzumab retreatment. ARR was low in each extension year (years 3–5: 0.22, 0.23, 0.18). Through 5 years, 75.1% of patients were free of 6-month CDW; 42.9% achieved 6-month CDI. In years 3, 4, and 5, proportions with NEDA were 52.9%, 54.2%, and 58.2%, respectively. Median yearly BVL remained low in the extension (years 1–5: −0.48%, −0.22%, −0.10%, −0.19%, −0.07%). AE exposure-adjusted incidence rates in the extension were lower than in the core study. Thyroid disorders peaked at year 3, declining thereafter.

          • I see. Why not report the real NEDA data? In theory, every patient on that trial could have had a relapse over a 5 year period

        • The two studies are very different CARE-MS I is a head to head with Rebif, whereas CARE-MS II had those who failed previous therapy. The brain volume loss data in CARE-MS I is year 1 -0.59%, year 2 -0.25%, year 3 -0.19%, year 4 -0.14%, year 5 -0.20%, year 6 -0.17%; for CARE-MS II year 1 -0.48%, -0.22%, -0.10%, year 4 0.19%, year 5 -0.07%, year 6 -0.10. The rate of brain volume loss in MS is -0.5% to -1.35% on average. Age -related brain volume loss is -0.20% at the age of 35 and -0.52% at 70y old. But, it must be born in mind that as the studies increase in years they lose participants calling into the accuracy of long-term data.

  • Hope for pwMS, why isn’t alemtuzumab used in in first line treatment for patients with high activity? Why EMA doesn’t approves alemtuzumab whenever a neurologist says it’s needed to treat bad cases ?
    Prof. G as done a plea to EMA regarding the need to use alemtuzumab as early as possible…
    Why ???

  • Do you suggest Alem. as a first line treatment in your practice?
    Do you think that an anti cd20 before Alem (and not only after) could help with secondary autoimmunity?

    • If the individual responds to an anti-cd20 alemtuzumab may not be needed. If you go in with alemtuzumab first, another treatment monitoring the repopulation of cells may be enough.

      • Doc, is it not the case that response to an anti CD20 is not the holy grail? i.e. relapse and MRI activity may be kept at bay but MS is still smouldering, brains are still shrinking, conversion to SPMS is not altered and long term use is questionable given the risk of infection etc. This is what i understand to be Prof G’s position on its use and part of the reason that patients on anti CD20 are now considering whether they would be better to switch to alemtuzumab whilst still early(ish) in their disease course

        • Comparatively the clinical trials are not head to head. Having said this, the rate of brain volume loss is slower with alemtuzumab. If you delay the start of both drugs with accrual of disability then the outcome is not great with if you go in early. The risk of infection with sustained immunosuppression is always greater than with induction therapies. These are individual decisions, but I agree many make them without really understanding what is happening at an immunological level.

        • MS is many things, but the immune system is evolutionarily designed to evade for good reasons. In cancer we have learnt to use engineered immune cells to fight the cells. Some want to use it inflammatory disorders, which in my opinion is bad news. This article that you linked references plasma cells – therapies already exist for this but whether they get into the CNS is another question.

  • Could I please have some advice? I have been battling with the decision for a medication switch for a few months now. This blog has been incredibly helpful.

    I have been on Tecfidera for approximately 2 years. I have developed approximately 7-8 brain lesions total (4~ish since starting Tecfidera) and I have 2 spine lesions (1 new one since starting tecfidera). Last contrast MRI showed no contrast enhancement.

    Is it better to start alemtuzumab or ocrelizumab? Clearly, Ocrelizumab is safer and my doctor says it could prevent me from having any lesions in the future. I understand alemtuzumab is the stronger medicine but I am nervous about my risks of developing side effects especially if both medicines could ideally do the same thing. I am mild in my disease course with just some numbness and minimal diplopia on extreme gaze.

    Thank you! I know this is long. This decision has been killing me.
    Best,
    Your fan

  • So waht happen if you do the oposite (ie: deplet Treg)

    Does the monocyte pools become more inflamatory ?

    Tthe mechanism will be the same?

      • This 🙂

        There is a specific protein called interferon gamma (IFN-?) that has powerful anti-tumor properties, including the activation of macrophages, which are cells that can initiate inflammation and prevent cancer growth.

        Bos’ latest study suggests that Treg cells suppress IFN-g production by CD4 T lymphocytes (a type of white blood cells), further instigating disease progression. After analyzing breast cancer models in which Treg cells had been targeted and destroyed, Bos discovered an increased presence of IFN-g and functional reprogramming of macrophages into tumor-fighting cells.

        Immune cell that drives breast cancer could be effective target in novel immunotherapies

        🙂

  • I started with tysabri. Was already noticeably disabled by then. I’d had undiagnosed ms for about 8 years at that point. Worked as well as possible until my jcv numbers went too high. On to Gilenya. Had a relapse that resulted in a large lesion close to my brain stem. The thing with that relapse was that I didn’t even have many symptoms, and they all went away. I guess it’s worth considering that (I could be wrong about this, but I think it’s true?) Gilenya controls T cells a bit.
    Next was ocrevus and after my 3rd dose I had a relapse that lasted for more than 4 months. My balance was horrible to begin with, like I could barely walk independently. I was very alarmed when an MRI done then said (for the very first time!) that my brain volume was less than expected considering my age or something like that. All of the ones that I had before then specifically said that it was normal for age.

    Post relapse my balance is still even worse. I’m walking independently but dang it can get scary. My fatigue is a lot worse too. Just walking across the makes room makes me feels like I’m going to die.
    Killing off all my B cells and letting my rogue T cells do their thing just doesn’t work for me 🙁
    I’m now supposed to start Lemtrada when my B cells get high enough. God only knows how long that will take. I wish so much that I had started with that. I know the possible side effects. The risks would have been worth it. Sorry for that rant :/

    • Sorry to hear that, MS is a nasty illness. There is a story in every person with MS and reminds me of why I chose MS as my specialist area and all the research that I do to better understand and treat this disorder. I hope things start to improve for you. NDG.

    • My wife made the decision to receive alemtuzumab as first line treatment (we live in Australia so no restrictions). The monitoring is intense (monthly blood and urine tests), even more so if you develop thyroid problems. My wife is currently dealing with a thyroid that is bouncing around all over the place. Over active now under active trending towards Hashimoto’s. With that said, we have a great endocrinologist and he is managing the situation well. She has completed year 1 and 2. No new lesions and no change in symptoms. My wife’s first symptoms appeared when she was 21 and was diagnosed when she was 37. Few relapses in between (double vision prompted the MRI and diagnosis). So, did she receive treatment early enough? Only time will tell. We formed the opinion to hit it hard irrespective of time from onset to diagnosis. At least we know that if she worsens, we did everything possible and can look at additional treatments once reconstitution is complete. Treatment is a personal choice and really depends on your tolerance to risk. My wife and I have no regrets.

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