Nature: ‘It’s all gone’: CAR-T therapy forces autoimmune diseases into remission

Argos said:
Could they cure allergies with this? Aren't they also caused by "rogue immune cells"? (Sorry if this is a dumb question)
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It's actually a very clever question. I am not sure that anyone has asked it and it makes sense.

Allergies depend on IgE committed B cells and their plasma cell derivatives. Nobody understands why a few people generate counterproductive IgE responses to very specific things like peanut protein. The plasma cells are likely to be long lived so therapies available up until now are unlikely to have had any obvious impact in the short term at least.
 
Argos said:
Could they cure allergies with this? Aren't they also caused by "rogue immune cells"? (Sorry if this is a dumb question)
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this is bispecific BCMAxCD3 targeting plasma cells, but there is as we mentioned CAR-T targetting BCMA so wont be surprised if used at one point too...or it curing allergies in people who receive it for autoimmune

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Sid said:
https://twitter.com/user/status/1726150131404226569


They won't. People who can pay will pay, the rest will be left to suffer and die.
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They have CAR-T brand in Australia costing $50K.. and I've heard of other places too, in general doesnt have to cost this much. For HSCT many pwMS and other autoimmune go to Russia and Mexico, that's the future of CAR-T too if the early results (in first half of 2024 i hope) for MS are encouraging, cos then will be big demand.
But we managed to find legit brands accepting autoimmune patients only in China for now, ... which imo is not that bad, they are in many ways w CART ahead of US/EU;, cos they have BCMA, the others dont. But China is challenging in so many ways
 
rvallee said:
In the discussions over the lower rates of mortality, I don't think I've seen once someone mention how a major part of this is that the people most vulnerable to COVID died, and there are fewer of them now since almost everyone's been infected.
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Me neither.

RedFox said:
This is a good description of the biographical disruption I faced due to ME, becoming ill at 21 while still in college.
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Me too. Got sick at 20. Meanwhile, 40 years and a completely trashed life later, with virtually no possibility left of having any of it restored, nor apparently even being allowed to live out my remaining days without the constant threat of arbitrary psycho-tyranny being visited upon me, and being blamed for it all, while the guilty not only get away with it but get rewarded for it,...

And the world wonders why we are angry? Real mystery, isn't it. You have to be wilfully blind in the extreme to not understand the problem here.
 
rvallee said:
In the discussions over the lower rates of mortality, I don't think I've seen once someone mention how a major part of this is that the people most vulnerable to COVID died
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Because I find this notable, first example I've seen yet, and it's from an immunologist.
B/c COVID is a whole-body disease w/ vascular, neurological, immune, & endocrine harms.

Less *acute respiratory* harm now, b/c:
a. the most vulnerable already died
b. we have some population immunity
c. Omicron is less severe than Delta

Much more diffuse harms instead ...
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As it was mentioned CD19 might not be enough for patients who have their illness run by autoantibodies produced by LLPC, so promising CAR-T is moving to dual CD19- BCMA target in autoimmune as well in US (in China CD19- BCMA was the target from start)
Autoimmune CAR-T: $AUTL Obe-Cel & BCMAxCD19 $AUTL Expansion into Autoimmune Space
Phase 1 SLE Trial: Planned for early '24 with obe-cel


 
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From lupusencyclopedia
Join us FEB 3 at 5PM EST for an online talk about CAR-T cell therapy in #SLE #lupus and other autoimmune disorders.

Also, see my latest blog post on:
CAR-T cells Made Simple
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https://lupusencyclopedia.com/car-t-cell-therapy-for-lupus/
LINK to event (this will be a Live FaceBook event): https://facebook.com/morethanlupus
you know that:
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22 out of 24 patients with severe SLE are now in remission, on no lupus drugs at all, and are doing great with few side effects after CAR-T therapy?
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Two of them have been in remission for over 3 1/2 years?
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2 of the 24 patients who were not in remission in a November 2023 report were too soon after therapy to see remission, but they were markedly better at 1 and 2 months after treatment!
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CAR-T cell thrapy has been also used in myositis, scleroderma, and myasthenia gravis with excellent results in all.
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What about #Sjogrens disease, which is a highly B-cell driven and CAR-T cells destroy B-cells. However, does this high B-cell load increase their risk for side effects, like complement reaction syndrome?
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Clinical trials are underway. Click on my blog post above to see links to see if you are eligible
Let everyone with autoimmune diseases know about this important event. Everything will be in easy-to-understand language.
Brought to you by
@LupusMore
, me
@lupuscyclopediaDid

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Jonathan Edwards said:
To get any reduction in autoantibodies from LLPC within say a year I agree that another target needs to be included. The pity is that protocols that produce profound hypogammaglobulinaemia have been around for over a decade - long before CAR-T panned out - but it seems that rheumatologists were too timid to grasp the nettle. Until we know how to discourage autoimmune clones selectively as far as I can see if autoantibodies are coming from LLPC then a period of hypogammaglobulinaemia is going to be needed to break a cycle and produce cure.

Of course most clinical immunologists assume that the drive is in CD4 T cells and they don't really believe that getting rid of B cell lineage cell alone is the answer, and that has been a major drag on progress. As I said, I very much hope CAR-T therapy will do what rituximab could not for autoantibody mediated conditions.

.
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Two questions regarding this
1) Why arent researchers and doctors exploring something like bortezomib which is cheap, and reduces both SLPC and LLPC specifically(alongside from what i understand red blood cells that make it an unpleasant drug, but nothing compared to the experience of ME/CFs or Long COVID frankly? Or maybe they are and I am just unaware
2) Out of interest regarding your question about the circular/causal relationship between CD4 T cells and autoimmunity, why arent researchers experimenting with something like rapamycin that seems to suppress CD4 in all the papers I could find, alongside the classic theraputic b cell approach? I realise that this leaves a patient quite severely immunocompromised, but three-six months of isolation is nothing to season ME/CFS and autoimmune patients frankly
 
Kitty said:
Simmaron Research is—there's info on their website about the pilot study they're planning.

https://www.simmaronresearch.com/rapamycin-trial
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I am on rapamycin and its helped a lot, thank god I have a doctor who is willing to work with me basically.
I am happy to see the trial definitely, I hope they are taking great efforts to separate patients who might have persistent/reactivated viruses screwing things up or it could end badly for them depending on the dose.

Please only take what I am saying here as n-1 and ultimately useless, but the best way I can describe rapamycin is that it helps immensely with brain fog, reduces the intensity by about 50% so im still impaired, but work is not the horror show it was (part time now due to long covid with substantial work accommodations from bed). I dont feel like its addressing the underlying issues though in terms of my POTS still being quite bad, and I can just feel that the drug gives me a little bit of light and hope by reducing the brain fog so much (ie: unable to count in my head before, now i can with much more ease but still not baseline), but not sorting out what is happening underneath. This is why I focus on b cell stuff and am starting a treatment soon based on this and some of the evidence from the norwegians.

Saying that a trial would be HUGE, if people could readily get what I get, I mean I was signed up to MAID and now my QOL is maybe from 10% to 50%, life is worth fighting for again. It would be incredible to see that happen for others and come from doctors, presumably within hemotology or rheumatology departments, fingers crossed!
 
Oh and just to add it definitely reduces my PEM, but its 100% still there. I can do weight lifting now, at my onset and prior to rapamycin I could not really walk so.......substaintial improvement, but still a long way to go
 
siobhanfirestone said:
Why arent researchers and doctors exploring something like bortezomib
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My understanding is that drugs like bortezomib can contribute to a combination regimen but on their own are not much good and toxic. I do not know why colleagues are not more aggressive with autoimmune disease in terms of combination regimens but I think it has a lot to do with them not really knowing what they want to do. The importance of B cells is still something that surprises people twenty years on. The assumption that CD4 T cells are in charge seemed very hard to wash out of the system.

siobhanfirestone said:
why arent researchers experimenting with something like rapamycin that seems to suppress CD4
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Maybe because depleting anti-CD4 antibodies and Campath-1, which cleared out almost all T cells for years does nothing for diseases like RA. The benefit of knocking out CD4 cells alone has been well and truly tested - it does not work. It might be worth adding in to a B cell depleting programme to prevent re-education of B cells perhaps but that starts to be quite a desperate strategy with compromise of both arms of the adaptive immune response without any clear theoretical base.
 
Jonathan Edwards said:
Maybe because depleting anti-CD4 antibodies and Campath-1, which cleared out almost all T cells for years does nothing for diseases like RA. The benefit of knocking out CD4 cells alone has been well and truly tested - it does not work. It might be worth adding in to a B cell depleting programme to prevent re-education of B cells perhaps but that starts to be quite a desperate strategy with compromise of both arms of the adaptive immune response without any clear theoretical base.
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I have seen trials and papers for separate arms definitely, like rapamycin in MS in the ways you describe which I belive (although i am not sure about this) is mainly focused on T cells and cykotine signaling as opposed to b cell activity (although i did find a lab study on rapa and BAFF but nothing in humans)? , : https://www.ncbi.nlm.nih.gov/pmc/ar...pamycin is considered a classical,MS (10, 11).

Do you mean by "quite a desperate strategy with compromise of both arms of the adaptive immune response without any clear theoretical base", that you do not believe there is enough evidence to combine a b cell treatment with t cell based stuff because of the lack of data and efficacy on t cells specifically? or a general scepticism of taking such a hard and potentially dangerous (with covid being everywhere) approach?
 
siobhanfirestone said:
Do you mean by "quite a desperate strategy with compromise of both arms of the adaptive immune response without any clear theoretical base", that you do not believe there is enough evidence to combine a b cell treatment with t cell based stuff because of the lack of data and efficacy on t cells specifically?
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Yes. There has never been any good reason to think there are abnormal T cell populations in most autoimmune states (the exception being AIR). In most autoimmune diseases abnormal T cell responses to relevant antigens are conspicuously absent. In coeliac there are T cell responses to a foreign antigen but even that seems to be an exception.
 
Jonathan Edwards said:
Yes. There has never been any good reason to think there are abnormal T cell populations in most autoimmune states (the exception being AIR). In most autoimmune diseases abnormal T cell responses to relevant antigens are conspicuously absent. In coeliac there are T cell responses to a foreign antigen but even that seems to be an exception.
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Ah ok thats very very interesting and somewhat surprising, and i guess why classic protocols have focused so much on b cell biologics. Thanks
 
siobhanfirestone said:
Ah ok thats very very interesting and somewhat surprising, and i guess why classic protocols have focused so much on b cell biologics. Thanks
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Or to be more precise, the protocols since 1998 when I first decided that it made more sense to target B cells. Up until then all the protocols were designed to target T cells - CD52, CD7, CD3, CD4. I could never understand why people thought targeting T cells made sense but it took me ten years to gather enough thoughts together to see precisely why it didn't and to see a specific mechanism of feedback that made B cell targeting make sense.

Even so Martin Glennie rightly pointed out that my first attempt at describing my B cell rationale was illogical and it didn't really have it clear in my head until after we had done the experiment and showed it worked.

A lot of drugs supposed to target T cells actually hit B cells too. The T cell theory was supposed to be supported by the PTPN22 gene link to RA but it turned out to be crucial for B cell receptor editing too.
 
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