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

[Trish]

@siobhanfirestone
Do you know more details about patient history / anamnesis and clinical picture & Symptoms?
Typical ME CFS (strict guidelines e.g. with PEM)?
How long sick ?
Measurements e.g. antibodies, etc?
Why was decided on Car-T ?
Which clinic was giving access to Car-T based on what (e.g. which markers?

Understanding each Anecdotal Remission of (specially) severe patients in detail is important.
(as we lack the proper research any other immune dysfunction illness has)

Please only post on the forum information that is in the public domain and add links to that public information. Speaking with my forum moderators hat on, we don't allow any individual patient's private information or personal medical details to be discussed here without their permission.

 

[Pibee]

A likely* legit brand of CAR-T is available outside of a trial, for SLE (and SS or other more severe autoimmune) indications in China, $100,000 for CD19, and CD19+BCMA is $150K.
*seems so but we're still assessing them!
In Mexico they barely even do it for cancers, as of recently, they buy brand from India, and there is this clinic in Tijuana mentioning CAR-T but it looked sketchy considering what I said about barely for cancers.
This is autologous CAR-T, there is also allogeneic which is way cheaper but the fear of severe cytokine release syndrome is bigger, especially in autoimmune. But it is all very interesting because allogeneic will survive shorter in the body so I think this makes risk of secondary T-cell lymophoma & other risks due to immunosupression lower. + accessibility/price.

Also, MS trials are starting too, I know Kyverna and Novartis are doing MS, not sure if anyone else.
This is interesting article: https://gavingiovannoni.substack.co...tle&isFreemail=true&r=1x3xe3&utm_medium=email

 

[Pibee]

The key point for me is that if ME were due to autoantibodies from short lived plasma cells the rituximab and CAR-T therapy should both show significant benefit - and rituximab didn't. If the autoantibodies are From long-lived cells CAR-T therapy might produce a noticeable effect after five years or so but that on its own is pretty unhelpful and no trial is likely to pick it up.
.

There are autoimmune studies with dual CAR-T that hits also LLPC, some case reports are already published.

18 cases with SLE cCAR-T with BCMA+CD19, it's a small biotech by USA based Chinese doctor, he told me BCMA Is absolutely needed for Sjogrens due to LLPC aabs... I've seen a number of cases both from German and Chinese where SSA stays positive with CD19 only. This could mean that SFN/dysautonomia part of Sogrens often requires LLPC target too.

I am not sure why Dr Yupo's longer follow up (max 4 years) case reports are fully ignored by the Western media as he presented it at EULAR a year before German professor Schett, in 2021, who actually gave his 1st patient CAR-T after he saw Chinese-American case report!

Also, IASO Bio, has BCMA alone and they published 13 case reports in NMO patients, 3 patients had Sjogrens as well.

Finally Gracell got FDA clearance for their dual CD19/BCMA FasTCAR. They also announced it will be a cheaper option because of fast production, but no other info.

 

[Jonathan Edwards]

There are autoimmune studies with dual CAR-T that hits also LLPC, some case reports are already published.

That makes sense. Though I would be doubtful that anyone can yet make definitive statements about Sjogren's which is a nightmare of a clinical category to work with.

My comments related to what I presumed was CD19 targeting. 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.

I am just not that convinced that ME is likely to be one of them. And if it is then we would need more than CD19 targeting to see any benefit in a time scale of under five years.

 

[FMMM1]

Apologies, trying to get my head around this.
So "rituximab induces an overall depletion of CD19+" i.e. short lived plasma cells since these express CD19+; similarly CAR-T therapy depletes CD19+ cells.

However, long lived plasma cells are CD19- so unaffected by rituximab & CAR-T therapy.
So basically you need another target to reduce long lived plasma cells.

Do immature long lived plasma cells express CD19+? Therefore, eventually (5 years +), you get a clinically relevant reduction in long lived plasma cells?

 

[Jonathan Edwards]

Do immature long lived plasma cells express CD19+? Therefore, eventually (5 years +), you get a clinically relevant reduction in long lived plasma cells?

It's a bit more complicated. Rituximab depletes CD19+ cells because CD19 and CD20 are largely expressed on the same population but that is B cells, not plasma cells. The reason ritxumab works (after 3 months) in RA or lupus is that if you remove B cells the short lived plasma cells die off after 3-6 months because they are not replaced by B cells maturing.

 

[Pibee]

Apologies, trying to get my head around this.
So "rituximab induces an overall depletion of CD19+" i.e. short lived plasma cells since these express CD19+; similarly CAR-T therapy depletes CD19+ cells.

However, long lived plasma cells are CD19- so unaffected by rituximab & CAR-T therapy.
So basically you need another target to reduce long lived plasma cells.

Do immature long lived plasma cells express CD19+? Therefore, eventually (5 years +), you get a clinically relevant reduction in long lived plasma cells?

Rituximab doesnt delete CD19 or CD20 positive cells deep enough, the significant % in tissue and lymph nodes stays and this is the most common reason why it fails when it does. You can hear that explained in prof. Schett's video I posted.
as the image shows.

After that long living PC are a reason and this is why many CAR-T brands target both CD19 and BCMA, and some do only BCMA (there is also mRNA brand where CAR-T cells survive in a body only a week)

 

[voner]

For SFN part of Sjogrens (which is where many undiagnosed MECFS patients fall) it is unclear for how many patients CD19 will be enough, as it is more responsive than the gland involvement, but less than SLE. For now 1 case report on POTS/sFN

@Pibee, thank you for posting that impressive video. I had to laugh at that I had to slow the video down to three-quarter speed to follow it! is it possible for you to expand on the quote above? You seem to place some emphasis on small fiber neuropathy diagnosis. if it’s possible to point us to some published information, that would also be helpful..

 

[Sid]

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


They won't. People who can pay will pay, the rest will be left to suffer and die.

 

[FMMM1]

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


They won't. People who can pay will pay, the rest will be left to suffer and die.

I had a brief look at the debate on treatments for cystic fibrosis and there e.g. some people, from UK, went to Argentina to buy the generic product (£25K/year) since the NHS refused to pay £100K for the patented product. The company, which owns the patent, didn't/couldn't patent in Argentina. NHS has indicated that it may evoke a wild card exception (war?); thereby forcing the company back into negotiations.
South Africa - there's a court case re whether the patent should be set aside.

So it seems there can be workarounds i.e. in some cases.

Drug costs roughly £5K/year to manufacture.

 

[Jonathan Edwards]

Rituximab doesnt delete CD19 or CD20 positive cells deep enough, the significant % in tissue and lymph nodes stays and this is the most common reason why it fails when it does.

That is one possible theory but the very first patient with RA treated with rituximab indicated that the situation is more complex.

Her B cells disappeared from circulation for about a year and then returned. But her rheumatoid and high titre rheumatoid factor antibodies returned five years later. That makes it unlikely that the return was due to B cell clones that had not been adequately cleared.

What most people working on this have not taken into account is the positive feedback loop dynamic that we need to explain the disease in the first place. The exact mechanism is not known but the likely scenario is that once rheumatoid factors of certain affinities and specificities are produced (likely targeting the CH2/3 domain junction) these 'educate' further B cells to produce rheumatoid factors with pro-inflammatory capacity - likely a quite different subset of autoantibodies that can form small immune complexes.

The implication of that is that if you leave behind plasma cells that can educate new B cell clones through their antibody products then no matter how deeply you deplete B cells the disease is likely to return - but quite likely not for a good while after B cells re-populate. We discovered early on that approximately 50% of patients relapse at circulating B cell repopulation but the other 50% ca remain in remission for up to 8 years before finally relapsing. That dynamic can really only be explained by a complex re-entrant loop.

So although there is no doubt that rituximab does not deplete completely in all (although there is evidence that it depletes more or less completely in some) it is very likely that to get remissions beyond five years (and I am not sure we have any data on that for CAR-T?) you are likely to need a plasma cell targeting agent as well.

 

[Pibee]

@Pibee, thank you for posting that impressive video. I had to laugh at that I had to slow the video down to three-quarter speed to follow it! is it possible for you to expand on the quote above? You seem to place some emphasis on small fiber neuropathy diagnosis. if it’s possible to point us to some published information, that would also be helpful..

From 2005 -2018 I thought I had MECFS, never heard of POTS or SFN. Then in 2018 I was diagnosed with that, and I figured I have Sjogrens because my SSA came borderline once and my aunt has Sjogren's, I had no dryness at all from 2005-2019, salivary gland ultrasound normal, ANA usually negative sometimes low 1:80 (only since 2018+, 2005-2018 was negative), but as I was told playing the Sjogrens card is better for getting IVIG i went to prove I have it, lip biopsy was also borderline (my lips were dry already), but it was badly performed so they said inconclusive, but yeah anyway, since my neurologist only cared abot SFN/POTS and not ME as they dont know what it is & cant be measued I just didnt mention anymore and then after IVIG my fatigue gradually went away, it overlaped with getting rid of GPCR from 5x high to 0 (on BerlinCures test too, but I dont know if that's what MECFS is, I am not claiming that, I am only sticking to a diagnosis we know what it is -SFN (to a degree).

I am just saying they cant tell us if CD19 CAR-T is enough for SFN, yet. I know only 2 people with POTS and SFN who did CAR-T , one says barely notices the symptoms of POTS since CD19 but her primary diagnosis was MG/AAG/LEMS, and the other did CD19+BCMA in China and didnt share any updates yet. But other antbodeis in Sjogrens tend to be more produced by LLPC , the CD19 in Germany didnt get rid of SSA aabs in SLE patients, and in China they also told me usually for Sjo BCMA is needed too.
I don't know about 5 years waiting for autoantibodies produced by LLPC to go away? What if it's 10? I am personally afraid to do only CD19, because if i need BCMA too later it will cost more + i need another chemo round.

 

[Jonathan Edwards]

I don't know about 5 years waiting for autoantibodies produced by LLPC to go away? What if it's 10? I am personally afraid to do only CD19, because if i need BCMA too later it will cost more + i need another chemo round.

The resistance of antibodies to nuclear protein antigens (Sm, RNP, SSA/B/Ro/La) to B cell depletion was identified by Maria Leandro in our first trial in lupus in 2000. The decay curves we had then suggest that half life for decay for LLPC produced antibodies is well beyond two years and likely 5-10. When I last looked at the literature the evidence on LLPC half life was still very unclear - very hard to establish.

I agree that at present it may be sensible to use a combination therapy. The only caution would be that experience 25 years ago with upgrading treatment with combinations made disappointingly little long term difference. We tried increasing the use of cyclophosphamide or more rituximab or more steroid and it didn't make much difference. I am optimistic that CAR-T might be a quantum leap towards cure but I also suspect that the optimum protocol will not be easily predicted. Moreover, it is likely to be different for different individuals. We had a few patients with quite profound hypogammaglobulinaemia, which ought to mean clearance of LLPC, but they relapsed much the same as others on stopping rituximab.

 

[siobhanfirestone]

@siobhanfirestone
Do you know more details about patient history / anamnesis and clinical picture & Symptoms?
Typical ME CFS (strict guidelines e.g. with PEM)?
How long sick ?
Measurements e.g. antibodies, etc?
Why was decided on Car-T ?
Which clinic was giving access to Car-T based on what (e.g. which markers?

Understanding each Anecdotal Remission of (specially) severe patients in detail is important.
(as we lack the proper research any other immune dysfunction illness has)

Yeah you are right, let me try and get back in contact with her and get as much info as possible. Obviously as is always the case single case studies need to be taken for what they are, and this isnt even a case study its a person online. Will report back with a fuller picture, i do know she had all the GCPR aabs from a celltrend test and that is what sent her down an autoimmune rabbithole (iirc she also didnt respond to rituximab)

 

[siobhanfirestone]

Please only post on the forum information that is in the public domain and add links to that public information. Speaking with my forum moderators hat on, we don't allow any individual patient's private information or personal medical details to be discussed here without their permission.

oh yes dont worry this will be respected

 

[voner]

I have a basic naïve question about this study. I noticed the patients are aged between 18 to 24 years old. Anybody have a guess as to why they are using such young patients? it a nature of the disease or because young people are more likely to have fewer complications with such an therapy, etc? @Jonathan Edwards?

 

[rvallee]

They won't. People who can pay will pay, the rest will be left to suffer and die.

One of the sad lessons of the pandemic is that although the classic moral dilemma of sacrificing one healthy person to harvest their organs and save many is the textbook version people think about, the real moral decision is closer to letting vulnerable people die so that healthy people can go on not thinking about it. What's shocking isn't just that it's happening, it's the intensity of it, the sheer scale. The whole "don't worry be happy" vibe about the pandemic has been so weird and illuminating, in a very bad way.

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. But in many cases the decisions were made overtly, like in Sweden where they euthanized the most vulnerable with opioids, so that respirators could be available for those with a higher chance of surviving.

In the end economics win, but bizarrely, medicine is very poor at leveraging the good side of economics. I see almost no international cooperation, almost no economies of scale or working together to solve big problems, like what we see in physics or even engineering. Except in rare cases like controlling tropical diseases, almost all decisions are local, and in many cases we see the bizarre phenomenon where each and every national health care system ignores what goes on elsewhere, to the point where they create local versions of the same thing, usually centered around their national culture. Not much different than having different temperature scales, as if water boiled differently in Finland or Brazil.

It's all a reminder of how primitive health care remains. In comparison to aviation, it's basically like pre-electronics. You can build an airline industry without electronics, but it's far from its full potential. Health care remains in that lower "barely threading above water" space because of how slow and lacking innovation is. And that's despite having super advanced stuff like CAR-T, which is like having both pre-electronics aviation industry and a space shuttle program at the same time, but it's like only the cutting edge is advancing, the rest of the industry barely makes progress over time. Basically none because of so-called evidence-based medicine and how much influence it has.

 

[Pibee]

I have basic naïve question about this study. I noticed the patients are aged between 18 to 24 years old. Anybody have a guess as to why they are using such young patients? it a nature of the disease or because young people are more likely to have fewer complications with such an therapy, etc? @Jonathan Edwards?

They picked young people on purpose because in the lupus mice model CD19 was enough only when early lupus, at later stages more autoantibodies are produced by LLPC thus CD19 wasnt enough. But there are also case reports of 3 older lupus patients, from Spain, with Novartis CD19 brand and for now it worked. It doesnt always remove all antibodies, that's the thing, it can still lead to remission depending which antibodies are actually giving you symptoms.

 

[Jonathan Edwards]

I have basic naïve question about this study. I noticed the patients are aged between 18 to 24 years old. Anybody have a guess as to why they are using such young patients? it a nature of the disease or because young people are more likely to have fewer complications with such an therapy, etc? @Jonathan Edwards?

I don't know but I can see how it might come about. Young people with autoimmune disease present a particularly tragic scenario - often unable ever really to transition from childhood to adult life, spending a lifetime as a dependent. That is not to say that things are not bad enough for older patients but The times when I was pressed hardest to make exceptions with early use of rituximab was for youngsters, some of whom would otherwise die.

For those below 18 the decision is even more fraught because they cannot reasonably be asked to consent to new treatments that might prove to have life-threatening side-effects. So I can see why a physician might end up recruiting 18-24 year olds.

Young people are also theoretically less at risk of immune depleting treatments. But I am not clear that that would be relevant. In general risk is perceived as going up after the age of about 60, not much before.

 

[RedFox]

Young people with autoimmune disease present a particularly tragic scenario - often unable ever really to transition from childhood to adult life, spending a lifetime as a dependent.

This is a good description of the biographical disruption I faced due to ME, becoming ill at 21 while still in college.