Thursday, 22 February 2018

Putting the CART before the horse: could CAR-T cells be a last-resort therapy in MS to rival HSCT?

First off, apologies my long winter hibernation from the blog. As you may have gathered (if anyone is paying close attention to my blogging habits) I'm no longer full-time at BartsMS, and have been working in mental health down the road at Mile End. There are loads of interesting things to say about the overlap between MS and mental health, lots of which have been discussed before on the blog. 



As well as the obvious overlap - disorders like depression, anxiety and cognitive impairment are more common in pwMS - I think there is a lot to learn from psychiatry about the whole approach to doctoring. From my limited experience, psychiatrists are better than us physical docs at thinking holistically about health, and at making proper shared decisions with clients - clients, rather than 'patients'. But I'll write more about this another time.



As you may be bored of reading by now, in the past few years it's become clear that B cells - the cells of the immune system that make antibodies - are heavily involved in the disease process. The most vivid piece of evidence for this is the effectiveness of ocrelizumab in dampening disease activity and disability progression. Ocrelizumab is pretty much a selective B cell-killing agent, so this implies that knocking out B cells is sufficient to disrupt the disease process. 



The problem with any drug that targets the immune system is that it will inevitably lead to 'off target' side effects. We think that a small proportion of B cells recognise something in the brain as 'foreign' and are responsible for driving the disease process - the ideal drug for MS would target these cells while leaving the vast majority of innocent B cells alone. This would presumably lead to fewer problems with long-term cancer risk and immunity against bugs.



While this is some way off, there is lots of exciting work going into selectively targeting particular cells of the immune system. An amazing technology which has been spearheaded by the cancer world caught my eye this week: the technology is called 'Chimeric Antigen Receptor T cells' or CAR-T cells. The idea is that each normal T cell carries a unique receptor which means that they are geared up to respond maximally to a specific particle, such as a bit of a virus or a bit of a bacterium. You can now make T cells in the lab to carry whatever receptor you want, and can therefore generate T cells that recognise and respond to anything. These cells are grown in the lab and then infused into the patient, stimulating a massive immune response against whatever target has been chosen. 



Several clever groups of scientists have generated CAR-T cells which specifically recognise and kill B cells. They've done this by making CAR-T cells which recognise CD19 - a marker present on the surface of all B cells. There are now two versions of these cells approved for use in the US for children with B-cell cancers. I read this very interesting paper this week about using CAR-T cells for a horrible B cell cancer which had not responded to first-line treatment.  It was extremely effective, producing remission in 81% of people at 3 months. As expected for a last-ditch therapy, it was also incredibly dangerous. About 3/4 of people had serious adverse events. 8/10 had what's called a cytokine storm - a severe systemic illness which often requires admission to intensive care. What is very interesting is that although the therapy led to lots of nasty short-term complications, people did not die of these side effects.



I'm blogging about this here because CAR-T cells, although dangerous, have the potential to be used for pwMS who do not respond to any of the normal highly-active therapies. I wonder if in the next few years this will come to rank alongside stem cell transplantation as an effective, albeit very dangerous, last-resort option for people who have tried everything else. 



I should emphasise that at the moment there is no evidence whatsoever that anti-CD19 CAR-T cells work in MS. Equally, these cells are still pretty broad-brush sledgehammers: they do not discriminate between different B cell subsets. They are particularly useful in B cell cancers in which the disease-causing cells are much more numerous in the blood than in MS. 



My hunch is anti-CD19 CAR T cells would be very effective in MS, but it is going to be difficult to justify doing a trial given how many safe and highly-effective alternatives are out there. It's likely that in the next few years more refined versions of this tech will come out that can target only certain subsets of B cells. 



Would you ever consider CAR-T cells if this kind of thing were available in the next 20 years?

25 comments:

  1. Interesting post. In a similar vein, use of an emerging technology the CRISPR cas9 system of gene editing could possibly target the B-cell sub population. Instead of engineering T-cell ag receptors, the sequence of DNA responsible for the aberrant B-cell activity can be spliced from the genome. It will be interesting to see the impact of these techniques.

    ReplyDelete
    Replies
    1. Agreed Crispr will be big in the next few years - the 'easiest' application I can see at the moment for it is in single gene disorders. The difficulty with MS is still that we do not know what the identity/ies of the autoantigens are and so we're still a way away from being able to target specific clones. The other problem is that editing BCRs and TCRs in vivo is v high risk - extremely difficult to predict antigen-specificity from the sequence, and high risk of bypassing tolerance and generating secondary autoimmune disease.

      Definitely an exciting area but think we need a bit more understanding of which B cells to target first before Crispr will be useful.

      Delete
  2. "Would you ever consider CAR-T cells if this kind of thing were available in the next 20 years?"

    This is one of the strangest question I've seen on this blog - and I've been reading it diligently for 7 years now.

    Are you saying that the trade off is short term non-fatal intensive care vs an 81% chance of a NEDA-3/4 life ever after? - if so, even good respondents on highly effective DMTs should consider this approach, particularly in light of the nuclear bomb meta analysis that was posted on this blog a couple of weeks ago and thrown quickly in the bin without any follow-up | link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686062/)

    So if we know that non of the current highly effective DMTs work really after the age of 40.5 (let alone age 53) - shouldn't we all solid patient able to withstand a cytokine storm give your idea a try when they hit this milestone?

    In other words, the risk/benefit paradigm of CAR-T should be assessed properly considering that the current armada is not a panacea, just a mere short term benefit in the early stages of MS

    The more serious question to ask: are you the right guy to champion a CAR-T study in MS?

    ReplyDelete
    Replies
    1. Apologies if it seems a silly question- I don't think it's silly because we currently have no evidence of benefit and very good evidence of the hazards. Hazards also underestimated in this kind of study as the life expectancy in this kind of aggressive B cell malignancy is so poor that we're not getting an idea of long-term safety

      Delete
    2. so, you've just answered the question: "Would you ever consider CAR-T cells if this kind of thing were available in the next 20 years?"

      Case in point.

      Delete
  3. "Talking about cancer is off topic"

    :)

    Guess i am not the only one :):)

    http://multiple-sclerosis-research.blogspot.com/2017/10/programmed-death-1-disappears-and.html#comment-form

    ReplyDelete
  4. Be careful :(

    "Abstract

    Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor–modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19+ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood–brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFN╬│, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity."

    http://cancerdiscovery.aacrjournals.org/content/early/2017/10/10/2159-8290.CD-17-0698#

    Obrigado

    ReplyDelete
    Replies
    1. Yes agreed v risky so far. These techs always get safer over time but at the moment it's still quite 'brute force'

      Delete
  5. Pd-1 immunne check point is seen in cancer microenvironment where at the border of the lessions t -cell look "exhausted"

    Cancer immunotheraphy of today research what they what to do is take

    the "brakes" of the immune system and just let go

    I am thinking about the recently aprooved new hype Car-t cell

    theraphy that do just that

    Of course no one knows what will be the side efects of turbocharged the immune system like that .Most likely new autoimmune disease on top of a cancer context

    However this is even more pressing in the context of ms as we dont need a overdrive immune system that can do us even more harm
    What will be the side efects of those engineer cd8 cytotoxic t cells in the context of ms?


    "T-cell exhaustion is a hyporesponsive state of T cells in chronic environment, with increased inhibitory receptors, decreased effector cytokines and impaired cytotoxicity.
    Most T cells in tumor microenvironment are exhausted, leading to cancer immune evasion.
    PD-1 is the major inhibitory receptor regulating T-cell exhaustion, T cells with high PD-1 expression lose the ability to eliminate cancer.
    Reversing T-cell exhaustion represents an inspiring strategy to treat cancer"

    http://www.nature.com/cddis/journal/v6/n6/full/cddis2015162a.html


    Obrigado

    ReplyDelete
  6. Be careful..part II

    Pd-1 immunne check point is seen in cancer microenvironment where at the border of the lessions t -cell look "exhausted"

    Cancer immunotheraphy of today research what they what to do is take

    the "brakes" of the immune system and just let go

    I am thinking about the recently aprooved new hype Car-t cell

    theraphy that do just that

    Of course no one knows what will be the side efects of turbocharged the immune system like that .Most likely new autoimmune disease on top of a cancer context

    However this is even more pressing in the context of ms as we dont need a overdrive immune system that can do us even more harm
    What will be the side efects of those engineer cd8 cytotoxic t cells in the context of ms?


    "T-cell exhaustion is a hyporesponsive state of T cells in chronic environment, with increased inhibitory receptors, decreased effector cytokines and impaired cytotoxicity.
    Most T cells in tumor microenvironment are exhausted, leading to cancer immune evasion.
    PD-1 is the major inhibitory receptor regulating T-cell exhaustion, T cells with high PD-1 expression lose the ability to eliminate cancer.
    Reversing T-cell exhaustion represents an inspiring strategy to treat cancer"

    http://www.nature.com/cddis/journal/v6/n6/full/cddis2015162a.html


    http://multiple-sclerosis-research.blogspot.com/2017/10/programmed-death-1-disappears-and.html#comment-form

    Obrigado

    ReplyDelete
    Replies
    1. Yeah engineering T cells / stimulating ex vivo is exciting. I guess the difficulty is ensuring that they are targeted in a rational way to disease-relevant cells/molecules. So anti-CD19s are a good example, the other example to mind is anti-EBV infected cells (https://www.aan.com/PressRoom/Home/GetDigitalAsset/12415).

      Delete
  7. Medimmune stopped development of its CD-19 antibody for MS. Was there a tox problem?

    ReplyDelete
  8. "What will be the side efects of those engineer cd8 cytotoxic t cells in the context of ms?"

    Pender was/is worried about more potent/numerous Tcells going into
    brain and increasing inflammation and worsening MS.But No bad results and a 60 y/o PPMS patient treated w/ 31% CD8+Tcell reactivity to EBV went from EDSS 5.0 to 3.5 in one year.

    Has any PPMS patient on Ocrevus ever improved in EDSS..?
    Moreover has any Drug ever improved EDSS in anyone with PPMS..?

    https://imgur.com/niGAJWi

    ReplyDelete
    Replies
    1. Yes the anti-EBV T cells are very promising as well, although so far quite small numbers and quite brief follow-up. The killer test will be to make CAR T cells which respond only to EBV-infected B cells. This is possible in theory but I don't know of anyone who is doing it.

      Agreed the EDSS improvement is impressive - I would add that EDSS is not a perfect measure of well-being but cannot argue with an improvement being impressive.

      Delete
  9. is it just me, or is this blog having much less OP participation?

    ReplyDelete
    Replies
    1. We are not sure what OP means? Do you mean Original poster?

      Delete
    2. Yes, Dr Benji in this case.

      Vitamin C for myelination in your case :)

      I thought that the whole idea behind posting less articles on the blog is to promote more debate - well that debate has to be moderated in my view....

      Delete
  10. If I'm not mistaken the Ofatumumab
    targets B cells, right?

    Does anyone know if Novartis intends to continue with Ofatumumab research?

    ReplyDelete
    Replies
    1. https://www.novartis.com/news/media-releases/novartis-confirms-leadership-multiple-sclerosis-ms-scientific-advancements-and

      Delete
    2. Humanized anti-cd20 ab similar to ocrelizumab. Ocrelizumab, ofatumumab are humanized while rituximab is chimeric and the side effects may be slightly different otherwise they are mechanistically the same.

      Delete
    3. Yeah I think there are a couple of trials ongoing -
      here's a head to head with teriflunomide. https://www.clinicaltrials.gov/ct2/show/NCT02792231?type=Intr&cond=%22Multiple+Sclerosis%22&draw=5&rank=1040

      Delete
    4. ofatumumab is human not humanised (human = mu i.e mumab) humanized is zu i.e. zumab and chimeric is xi i.e. ximab.

      Delete

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