Wednesday, 3 May 2017

#ThinkSpeak: immune rejuvenation therapy

Anti-CD20 vs. the PIRTs, who will win? #ThinkSpeak #MSBlog

Apologies to pwMS who don't have a science background, you may find this post a bit heavy going. However, it is important for you to understand the information in this post as it may inform your decision to be treated with a non-selective, or semi-selective, PIRT (pulsed immune reconstitution therapy), for example alemtuzumab, cladribine or HSCT, rather than going with an anti-CD20 therapy. 

Earlier this week I asked the question whether or not you need a PIRT to deplete both T and B cells, or if you could get away with a simpler B-cell therapy. I made the point that if the Pender hypothesis in relation to EBV is correct then T-cell depletion followed by reconstitution may be important. I have hypothesised that PIRTs may rejuvenate important anti-viral responses, in particular the anti-EBV, CD8+ or cytotoxic T-cell responses, which potentially play a very important role in MS. What is the evidence for this? 

The paper below by Muraro and colleagues on immune function post-HSCT suggest a non-selective PIRT (T & B cells) may rejuvenate your immune system. They show that HSCT has distinctive effects on CD4+ and CD8+ T cell repertoires. A immune repertoire in this context refers to the diversity of the immune cells in the peripheral blood, in other words how many potential memory T-cells there are to fight infections or cancers. 

In relation to the CD4+ T cells, dominant TCR (T-cell receptor) clones present before treatment were undetectable following reconstitution, and patients largely developed a new repertoire. In other words HSCT ablated these clones, which is a good thing if they are responsible for driving autoimmune disease, i.e. MS. 

In contrast, dominant CD8+ clones were not effectively removed, and the reconstituted CD8+ T cell repertoire was recreated by clonal expansion of cells present before treatment. What is not answered in this study is whether or not these cells are more responsive to their target, for example against cells infected with EBV. We know that in pwMS the EBV reactive CD8 + cells are senescent, tolerant or burnt-out and simply unable to mount an effective response against EBV. Michael Pender hypothesises that this is the cause of MS, i.e. these cells are unable to enter the CNS (central nervous system) and kill EBV infected B-cells and plasma cells that are driving MS pathology. 

It is important to note that in the study below that patients who failed to respond to HSCT had less diversity in their T cell repertoire early during the reconstitution process. In other words the PIRT did not have the desired effect on rejuvenating the immune system. 

If this hypothesis is correct then anti-CD20, or anti-CD19, or BTK (Bruton Tyrosine Kinase) inhibitors that simply target B-cells may not be the best treatment option for MS. In other words it is not good enough to simply target the EBV reservoir, but we need to rejuvenate the T-cell response to EBV to control MS.

How does a non-specific (alemtuzumab, HSCT) PIRT, or semi-selective PIRT (cladribine), do this compared to a selective B-cell depleter? It is by immunological escape. When the immune system is depleted it allows viral reactivation to occur, i.e. EBV wakes up and starts replicating. We know this happens quite commonly with PIRTs. The viral reactivation is important because it results in viral protein production that then boosts the immune response when the immune system starts recovering. This is like a natural vaccine. This idea is not new and has been muted as a possible treatment for  chronic viral infections, for example in HIV, and underlies the theory of using drug holidays to allow viral reactivation to boost endogenous immunity against the virus.

The implications of this hypothesis are not trivial. If this hypothesis is correct then the anti-CD20's as a class of treatment won't be the treatment of choice for MS, PIRTs (T & B cell depleters) will become the treatment of choice. I therefore urge any researchers reading this post to design and run experiments to test this hypothesis. PwMS won't thank us if they find themselves with progressive brain atrophy and increasing disability 5-10 years after starting an anti-CD20 therapy when they turned down the option of a PIRT early in the course of their MS. 


Muraro et al. T cell repertoire following autolous stem cell transplantation for multiple sclerosis. J Clin Invest. 2014 Mar;124(3):1168-72. 

Background: Autologous hematopoietic stem cell transplantation (HSCT) is commonly employed for hematologic and non-hematologic malignancies. In clinical trials, HSCT has been evaluated for severe autoimmunity as a method to "reset" the immune system and produce a new, non-autoimmune repertoire. While the feasibility of eliminating the vast majority of mature T cells is well established, accurate and quantitative determination of the relationship of regenerated T cells to the baseline repertoire has been difficult to assess. 

Methods & Results: Here, in a phase II study of HSCT for poor-prognosis multiple sclerosis, we used high-throughput deep TCR╬▓ chain sequencing to assess millions of individual TCRs per patient sample. We found that HSCT has distinctive effects on CD4+ and CD8+ T cell repertoires. In CD4+ T cells, dominant TCR clones present before treatment were undetectable following reconstitution, and patients largely developed a new repertoire. In contrast, dominant CD8+ clones were not effectively removed, and the reconstituted CD8+ T cell repertoire was created by clonal expansion of cells present before treatment. Importantly, patients who failed to respond to treatment had less diversity in their T cell repertoire early during the reconstitution process. 

Conclusion: These results demonstrate that TCR characterization during immunomodulatory treatment is both feasible and informative, and may enable monitoring of pathogenic or protective T cell clones following HSCT and cellular therapies.

CoImultiple

34 comments:

  1. Wow! I think you are onto something here. It may not be a black swan, but is clearly more gray than white. Let's hope you are correct

    ReplyDelete
  2. ProfG, you just published a paper on memory B cells and showed data suggesting that ocrelizumab could be a PIRT, is that wrong?

    ReplyDelete
    Replies
    1. It's a matter of terminology. Do you call long term depletion of a -
      relatively - specific cell type (say B lymphocytes) with subsequent recovery 'immune reconstitution' (as we've done in the B cell review, though under a different name - induction therapy), or does it have to be 'all' lymphocyte populations? However, why calling solely 'lymphocyte' depletion immune reconstitution when alemtuzumab & cladribine leave other cell types virtually unaffected; HSCT is a much broader immunosuppression/-reconstitution approach and probably matches the definition of a PIRT most comprehensively.

      Delete
    2. You can blame me for the phase II extension data, also cladribine is not a good CD8 depleter either. However these hypothesis are testable.

      The restricted repertoire that develops after alemtuzumab was claimed to be the rerason for autoimmunity

      Delete
    3. Yes, ocrelizumab is a selective B-cell PIRT. It does hit a small population of T-cells, which may be significant. However, the way it has been developed is not as a PIRT but a maintenance therapy, i.e. a continuous therapy.

      HSCT and alemtuzumab are non-selective PIRTs as they also take-out the innate immune system (neutrophils, monocytes and NK cells), which exposes treated patients to acute bacterial and fungal infections, e.g. Listeriosis. Cladribine, in comparison, is semi-selective in that it takes down B and T cells and leaves the innate immune system relatively unscathed. This is why we don't see Listeriosis and other bacterial infections with cladribine.

      Delete
  3. So with the optionality in mind, one is better off switshing from a maintance agent to PIRT as soon as practical?

    ReplyDelete
  4. "PwMS won't thank us if they find themselves with progressive brain atrophy and increasing disability 5-10 years after starting an anti-CD20 therapy when they turned down the option of a PIRT early in the course of their MS. "

    How do the brain atrophy figures of patients responding to Alem/HSCT compare to CD-19/20 responders (Natalizumab)?

    ReplyDelete
  5. I see it as a no brainer , why not go with Alem or HSCT as results are there and these two options are currently the best available right ? Ocrelizumab just isn't showing brain atrophy results,why wait ?

    ReplyDelete
    Replies
    1. because it's just another hypothesis. A real brainer actually.

      Delete
  6. Makes perfect sense to me given HSCT and alemtuzumab give the best long term remissions. Also they both decimate the existing immune system. Only problem given NHS will only fund to 2 treatments. What happens if you need 3 or 4 or even 5? Do you then take something like daclizumab. I'm waiting for a dare for my alemtuzumab. Shortage of beds. Can I get the bed on my private insurance and drug on NHS to Bypass waiting lists?

    ReplyDelete
    Replies
    1. Cladribine, all the benefits without the negatives of the above. Just sayin'!

      Delete
    2. Unfortunately, cladribine doesn't bat in the same efficacy league; we compromised on the dose to make it safer. However, at an individual patient level there is a lot to be said for cladribine if you turn-out to be one of the long-term responders.

      Delete
    3. ProfG, based on your trial data why do you say that it does not bat in the same league as Alemtuzumab the effects look pretty similar? Surely both bat below HSCT.

      Delete
    4. Cladribine has a relative reduction in annualised relapse rate of ~55% relative placebo vs. Alemtuzumab ~50% relative to IFNbeta (Rebif) and AHSCT has not been compared to anything except mitoxantrone in an under-powered study. NEDA rates are difficult to compare because different populations were studied and epochs for comparison are different. When it comes to brain atrophy rates alemtuzumab and AHSCT are in the same zone. Unfortunately, we don't have cladribine data beyond two years, but the atrophy rate in year-2 is not as good as that what is seen with alemtuzumab and AHSCT.

      Because we don't have head-2-head trials is this all indirect comparisons. This is why we want to compare alemtuzumab vs. AHSCT and why we tried to get a cladribine vs. alemtuzumab trial funded. Let's hope the NIHR funds the former.

      Delete
    5. You may have answered this question in a previous post. Apologies for singing the same rhyme again:

      How does the 2 yr brain atrophy data compare between alemtuzumab and natalizumab please?

      Sorry again for making you repeat your self.

      Delete
  7. After alemtuzumab or in place off? It's brain atrophy stats are not as good. Whereas brain atrophy in alemtuzumab is less than even normal population. Quoting Dr Aaron Boster..

    ReplyDelete
  8. Great post, we need to see comparisons of the big players. Ideally with trials but in the interim it's interesting to read about why T-cells may need to be targeted.

    Prof G, theoretically, is AHSCT better than Alemtuzumab? I would think so considering AHSCT enters the CNS, whereas Alemtuzumab doesn't...

    ReplyDelete
    Replies
    1. AHSCT only gets in CNS if the drugs used to deplete get in the CNS

      Delete
    2. Most protocols I'm aware of use cyclophosphamide. This enters the CNS, yes?

      Delete
    3. Yes cyclophosphamide does get in.

      Delete
    4. So then in answer to my question, theoretically is AHSCT more efficacious than Alemtuzumab? Or is destroying the cells in the CNS not necessary?

      Delete
  9. It sounds like you feel strongly about this.

    Thank you for the entry.

    ReplyDelete
  10. If this is correct... it doesn't even matter if alemtuzumab doesn't enter the CNS?... you really don't need to kill those long lived plasmatic cells?

    ReplyDelete
  11. This is so timely. I have low(ish) WBC due to Tecfidera and am being encouraged to consider an alternative. I am in a quandary as to which approach to go for or just to argue for sticking it out on Tecfidera for a while longer. The SPMS conversion rate from Ocriluzimab/Rituximab would be something that could sway me one way or the other but it doesn't seem to be readily available.

    ReplyDelete
  12. ''Makes perfect sense to me given HSCT and alemtuzumab give the best long term remissions. Also they both decimate the existing immune system. Only problem given NHS will only fund 2 treatments. What happens if you need 3 or 4 or even 5? Do you then take something like daclizumab''

    Can someone please respond to this particular post.

    Prof G posted about the fact that Alemtuzumab was costed on 3 courses and that only 40-50% respond to two which makes two courses a potential waste of money leading to the need to start another drug which could cost more in the long run.
    If a third Alemtuzumab is never funded what would a Neuro suggest? This post mentions Daclizumab. Is there still a place for Mitoxantrone which does not have funding restrictions or would that be a bad mix following x2 Alemtuzumab?

    Thanks

    ReplyDelete
    Replies
    1. Based on the CARE MS of the people followed up about 50 percent needed a third course, and a number require a forth course.

      The neurologists are at the ABN isn't this something that should be debated rather than some Benal company sponsored thing.

      In fact why was such a session sponsored. Probably breaks the rules.

      The data is there in Tuohy et al that three courses value many the neurologist should read this.

      Daclizumab is a lower efficacy agent than alemtuzumab But first question to answer is are the Babs made by alem cross reactive to dac, if they are it is going to be a problem as most people taking alem have babs.

      As we said when you start a treatment you have to think what the switch will be. Discuss this with your neuro. Will they give the third infection.

      What happens post alem is a tricky one mitochondrial has a life span has it carries cardiotoxicity. Generic cladribine maybe ocrelizumab if nice approve.

      However this is the type of thing that should be discussed at ABN to get guidance.

      Delete
  13. How does this work with ocrelizumab's success in progressive ms?

    ReplyDelete
  14. Professor Giovannoni, I appreciate you raising this possible theory and truly appreciate everything you do, but I just don't understand how this squares with the observed data.

    Across many measures, ocrelizumab appears to be in the same league as alemtuzumab (disability progression, relapse rate, lesions), which leads to amazingly high NEDA-3 rates (>80%). The reduction in brain atrophy from OCR appears to be about 25% relative to INFB-1a with a trial that had 75% treatment naive patients. This is roughly in the same league as the two alemtuzumab trials. CARE-MS I (treatment naive) had a 40% drop, and CARE-MS II (prior treatment) had a 25% drop. If you weight that out to compare fairly, maybe alemtuzumab has a 36% drop vs ocrelizumab's 25%. This is a decent numeric difference, but given the variability and complexity of measuring atrophy, it's hard to know if this is really material (especially given the other metrics).

    The stories about long-term rituximab patients converting to SPMS is concerning, but the only published story I can find is a patient who began using rituximab well after diagnosis, for just a few years, and with evidence of disease activity. This fits exactly with the axon-length-dependent progression hypothesis Prof G has stated multiple times - this patient had accumulated too much damage and ended up progressing anyways. Dr Hauser's claim that many of his patients have converted to SPMS is scary, but again, we have no data to back this up, no understand of who was treated with rituximab in the first place, etc. It also doesn't make sense given ocrelizumab was the first drug to ever show impact on progressive MS.

    I feel like the argument presented thus far, Prof G, is based on theory without data showing why it's true. This is frankly worrying me that neurologists like yourself have information that is not being shared with the public and causing these cryptic warnings that ocrelizumab will not be as effective as we hoped. I haven't known you as someone who would jump to conclusions, and you seem pretty convinced of this argument.

    Just know that there are hundreds if not thousands of your patients (I see you as just as much of an advisor as the neurologist whose office I visit) who are thinking about or in the process of moving to ocrelizumab. We've put our trust in you to give us the right information, so if you truly believe that picking alemtuzumab versus ocrelizumab is literally a matter of brain-survival or death, you owe it to us to lay out the case!

    ReplyDelete
  15. Does this mean Alemtuzumab will be effective in progressive ms and more so than ocrelizumab? If so why hasn't it been used in trials for progressive ms?

    ReplyDelete
    Replies
    1. I suspect we will never know. Based on AAN abstracts an alternative to alemtuzumab is being tested in progressive MS.

      Based on early open label non controlled studies it was evident that many people continue to progress. So the myth was created that progressive ms does not respond to immunosuppression. Ocrelizumab has burst this myth.

      If you load your trials with active progressive MS I bet alemtuzumab will work to some extent.

      However is this success going to be detrimental. Now ocrelizumab has a licence for all of PPMS and not active MS the incentive to find a treatment is reduced.
      Will ethics committees say do a head to head with ocrelizumab (adding millions to cost) as it is not ethical to give people with progressive MS nothing.

      Delete
    2. Lol. I’d argue that HSCT data should have burst that myth in the minds of neuros: but blah blah blah *insert excuse of choice*. I must either be a genius (unlikely) or there must be something in the countless papers on HSCT for MS published between 2011 and end of 2015/early 2016, that led me to form the same conclusions about progressive MS and the efficacy of immunosuppressive treatment on MS (Including HSCT) that have been argued in this blog in the context of ocrelizumab.

      Back in 2015, I concluded that neuros don’t even know what progressive MS let alone to actually recognise it in all but the black and white cases.

      Delete
  16. So exciting to read all of this!
    So, if correct, in lay terms we need to

    a) wipe out ebv infected Bmem so they don't produce anymore ebv infected autoreactive plasma cells. Alemtuzumab takes out Bmem and plasma in periphery but doesn't reach Bmem in CNS? Cytotoxic used in HSCT does. As does cladribine but less so. Maybe amount of derisking cladribine dose should be very much personal medicine?

    b) deplete ebv reactive CD8 T as they are aged and tired. But CD8 T must then recon asap so can react to ebv. Clonal expansion no good as just get more tired ones. How to stimulate new ones??


    So kind of ironic, far from T cells driving disease, shouldn't depleting CD8 longterm make MS worse? Surely aged tired ebv CD8 better than no CD8?

    Sorry for rambling, just trying to get layperson handle on all this ;-)

    Making me more determined than ever to start treatment with cladribine. And maybe not worry too much about level of lymphopaenia? Will see what haematologist says next week ;-)












    ReplyDelete
  17. Many patients have been on rituximab for years
    What advice would you give to them?

    You said: "PwMS won't thank us if they find themselves with progressive brain atrophy and increasing disability 5-10 years after starting an anti-CD20 therapy"

    After over four years on rituximab, with no relapses or progression, I'm worried now.
    Not just by this post, also because longterm safety is such an unknown




    ReplyDelete
  18. Ocrevus is here now, and that is good I suppose

    However, even after all these years, I'm still horrified that the rituximab trials were discontinued.

    Rituximab has worked miracles for people who used it off-label. The tragedy is the number of people is so small.

    It could have helped so many people. But their doctors/health systems did not consider/offer/advise/approve offlabel use


    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.