Tuesday, 13 June 2017

Alemtuzumab kills B cells. Not Really a Stepford Wife

So we talked about our new paper that came out yesterday. 

David Baker; Samuel S. Herrod, Cesar Alvarez-Gonzalez, Gavin Giovannoni; Klaus Schmierer Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurol. Published online June 12, 2017. doi:10.1001/jamaneurol.2017.0676

IMPORTANCE Alemtuzumab, a CD52-depleting monoclonal antibody, effectively inhibits relapsing multiple sclerosis (MS) but is associated with a high incidence of secondary B-cell autoimmunities that limit use. These effects may be avoided through control of B-cell hyperproliferation.
OBJECTIVE To investigate whether the data describing the effect of alemtuzumab on lymphocyte subsets collected during the phase 3 trial program reveal mechanisms explaining efficacy and the risk for secondary autoimmunity with treatment of MS. 
DESIGN, SETTING, AND PARTICIPANTS Lymphocyte reconstitution data from regulatory submissions of the pivotal Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I and II (CARE-MS I and II) trials were obtained from the European Medicines Agency via Freedom of Information requests. Data used in this study were reported from June 22 to October 12, 2016. 
MAIN OUTCOMES AND MEASURES Tabulated data from T- and B-lymphocyte subset analysis and antidrug antibody responses were extracted from the supplied documents. 
RESULTS Alemtuzumab depleted CD4+ T cells by more than 95%, including regulatory cells (−80%) and CD8+ T cells (>80% depletion), which remained well below reference levels throughout the trials. However, although CD19+ B cells were initially also depleted (>85%), marked (180% increase) hyper-repopulation of immature B cells occurred with conversion to mature B cells over time. These lymphocyte kinetics were associated with rapid development of alemtuzumab-binding and -neutralizing antibodies and subsequent occurrence of secondary B-cell autoimmunity. Hyperrepopulation of B cells masked a marked, long-term depletion of CD19+ memory B cells that may underpin efficacy in MS. 
CONCLUSIONS AND RELEVANCE Although blockade of memory T and B cells may limit MS, rapid CD19+ B-cell subset repopulation in the absence of effective T-cell regulation has implications for the safety and efficacy of alemtuzumab. Controlling B-cell proliferation until T-cell regulation recovers may limit secondary autoimmunity, which does not occur with other B-cell–depleting agents.

I get accused of being too scientific so I thought I would explain the contents of the papers so I am going to spend a few days explaining this paper.

For the "Headmaster" who can only read a few lines before moaning:-), here is the take-home message

Highlights:

  • Alemtuzumab works in MS because it depletes memory B cells

Want to understand more? ... Sit down and read on

How does alemtuzumab work? 

Simple you say, it works because it depletes T cells.


Yes if you look it is very evident that T cells are depleted for a long time. 


It is obvious because this was shown in 1999 (See above).


Coles AJ, Wing M, Smith S, Coraddu F, Greer S, Taylor C, Weetman A, Hale G, Chatterjee VK, Waldmann H, Compston A.

Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet. 1999;354(9191):1691-5.

But there may be an "elephant in the room" staring you right in the face, it has been published a number of times, but largely ignored, as MS was thought to be a T cell problem.


However, as time went by and clinical trials started the elephant began to be airbrushed.


If you look at the Green line (above), Can see anything?


It going back to normal in 3-6 months. But what happens between 6-12 months?


It is clear there is an "overshoot". 


However, the airbrushing began from the time of the phase II trials and rather than showing the data in the way presented above, it began to be shown as time to normality. This reports the time when B cells got back to normal levels. 


The "overshoot" ignored and unmentioned and so by the time of the pivotal phase III trials, you get get the time to normality of B cells by 6 months and T cells are near normal by 12 months (Cohen et al. 2012, Coles et al. 2012).   


Lets' forget about earlier studies suggesting it may take 2-3 years for that to happen to CD4 cells.


However, what happened to the overshoot?...Not mentioned and so not surprising if you don't think about it.


Why does alemtuzumab cause B cell autoimmunities?

Ocrelizumab and cladribine deplete B cells but do not cause an overshoot and they do not cause the secondary autoimmunities associated with alemtuzumab.

So now we appear to have the "Don't mention the Overshoot" and then apply the "Stepford Wives"  logic. Then it all looks OK.


Stepford Wives Logic

This is when the Wives disappear and come back as perfect robot copies that look just like the wives. Just like the CD19 disappear and CD19 come back by 6 months.

However in Stepford, the wives are obedient slaves, so they are not really the same as when the husbands started to robotise their wives in the first place
















                                                       Nicole Kidman in Stepford Wives

So if we look at the green line above, it implies that at 6 months, the CD19 B cell population is the same as the beginning and so MS can't be a B cell problem, because alemtuzumab works for more than 6 months and the autoimmunities normally take more than 6 months to show. 

MS is a T cell disease
Smoke Screen Created 

However, this makes the assumption that analysis of CD19 B cells is picking up one population of cells. 

However, it isn't. 


It is a composite of different cell types 
So as soon as you deplete with alemtzumab, 


  • immature B cells (CD19+, CD38+, CD10+) come streaming out of the bone marrow to fill the space in the blood, created by depletion caused by alemtuzumab. 
  • They then convert to naive/Mature B cell (CD19, CD38+, CD10-), way above baseline. 
This happens after HSCT.

So why is the total CD19 B going up between 6-12 months by only 30-35%?

Simply, because there is a population of B cells that is being depleted out of sight.


These are the memory B cells (CD19+, CD27+). 


We said about a month ago that these are good candidates for why MS is blocked by alemtuzumab. 


Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K.Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017. pii: S2352-3964(17)30045-2. doi: 10.1016/j.ebiom.2017.01.042.


Therefore, if you were to look properly at the "Stepford Wive " B cells as they return they don't look anything like the original population at 6 months. So suggest that this is normality is perhaps misleading and far from the reality. 

They are immature robots ready to cause mayhem.


                                     Is this really Nicole Kidman?
In the trial data, the CD8 (a mixture of types) cells recover to the lower limits of normal after 6-12 months.

CD4 stay low as do the B memory cells throughout the duration of the phase III trials. 

So do you choose CD4 T cells, and stick with the dogma, B cells or both.

The data is consistent with a direct effect on B cells as the reason why alemtuzumab works. If you are interested read on... (Click).

So now you know how alemtuzumab may block MS, we can now address why it causes B cell autoimmunities.

15 comments:

  1. Fantastic- you've worked you little cotton socks off, and really set the cat among the pigeons! I expect there is a lot of squawking going on as I type

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  2. As a newly diagnosed MSer and having had first round of alemtuzamab, reading this is a bit over my head but on the whole is good...is that right? Would you consider it to be as effective as hsct and/or have there been comparison data published looking at it?

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    1. Alemtuzumab is amongst the most effective treatments that is currently available and so many it people it was given them many years of "disease free" activity.
      This paper explains this. I will be spending all of this week doing posts that will help explain this paper

      There has been no head to head but the No evidence of disease activity of HSCT is better I would say. But Irriterate alemtuzumab is a very effective drug.

      However it comes with problems one you should be very aware of and that it can cause unwanted autoimmunities in about 50% of people with 5 years. These also occur with HSCT in MS but less commonly. Perhaps the company could have done more to reduce this risk

      The other problem that this study exposes is that anti-drug response generates in many people. Cambridge recognised this and created a way to reduce this.
      We show that in the first year the occurrence before the next infusion is very small, although not in the paper I have reasonable evidence that at least one out of about 400 people did not respond well to the second cycle because of this. However if you need a third cycle I suspect the risk of the drug not working well is increased (thirty fold) as and so you need to look at your bloods to ensure the drug is working. Genzyme have the data to know how small that risk is, they need to be open about this and this paper will help in that process. If the drug isn't you need to switch.

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    2. Weird question MD but what happens if someone undergoes HSCT after having had Alemtuzumab? We know people treated with Alemtuzumab have significantly lower levels of certain types of T cells for 20 + years after initial treatment. Would that be the case if they underwent HSCT or would HSCT reset that?

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    3. It happens loads of times as alemtuzumab has been used as the depleting agent in HSCT. If you are having ablative HSCT, you kill every thing alemtuzumab being one way to do this and you start with the stem cell and everything repopulates from there.

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    4. Interesting MD, thanks for the response!

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  3. Excellent explanation MD o//

    And post Alemtuzumab to avoid secondary autoimmunity could be given to Cladribine or would have to be the same Rituximab? But if given the rituximab could not there be the risk of NABs as well?

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    Replies
    1. Possibility but it will take out some T cells and a few Tregs which one wants to get up as quick as possible

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  4. "They are immature robots ready to cause mayhem"

    Are you refering breakthrough disease? or secondary autoimmunity ?
    Thanks Luis

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  5. Ok...So if B cells are like a time bomb really to atack other organ of the body
    When are they gonna atack the cns (again)? They lost memory?

    How long will it take to get memory back?
    Thanks
    Luis

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