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

Sid said:
CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-up

  • Fabian Müller, M.D.,
  • Jule Taubmann, M.D.,
  • Laura Bucci, M.D.,
  • Artur Wilhelm, Ph.D.,
  • Christina Bergmann, M.D.,
  • Simon Völkl, Ph.D.,
  • Michael Aigner, Ph.D.,
  • Tobias Rothe, Ph.D.,
  • Ioanna Minopoulou, M.D.,
  • Carlo Tur, M.D.,
  • Johannes Knitza, M.D.,
  • Soraya Kharboutli, M.D.,

Abstract
BACKGROUND

Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission.

METHODS
We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology–European League against Rheumatism (ACR–EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded.

RESULTS
The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR–EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell–associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization.

CONCLUSIONS
In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.)

https://www.nejm.org/doi/full/10.1056/NEJMoa2308917
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I don't have access but from what I saw in the news reports the first patients underwent treatment in March 2021, i.e. apart from the 2 year follow-up data in the paper, the authors will soon have data reaching 3 years back.

"It is already possible to use CAR-T cell therapy in other patients with severe forms of systemic lupus erythematosus, systemic sclerosis and myositis as part of the so-called CASTLE study, which is being conducted at the University Hospital Erlangen. Those affected can write to the e-mail address Car-T-Cell.UKER(at)uk-erlangen.de." (translated via deepl from the above news report)." Unfortunately I couldn't find much additional information on the CASTLE study.

The list of authors is quite long, but Georg Schett and Andreas Mackensen seem to be the ones leading this project.
 
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EndME said:
I don't have access but from what I saw in the news reports the first patients underwent treatment in March 2021, i.e. apart from the 2 year follow-up data in the paper, the authors will soon have data reaching 3 years back.
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The paper says the following:

From February 2021 through May 2023, a total of 15 patients with refractory systemic autoimmune diseases (8 with SLE, 3 with idiopathic inflammatory myositis, and 4 with systemic sclerosis) were treated with CD19 CAR T cells.
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The accompanying editorial delves into why this works better than CD20 depleting drugs like rituximab.

CAR T cells that target the CD19 antigen have provided a paradigm shift in the management of certain B-cell–derived lymphomas and leukemias.2 These autologous T cells, genetically manipulated to seek out their targets, are also potently cytotoxic. In the short term, treatment may be associated with cytokine-release syndrome and reversible neurotoxic effects; longer-term adverse effects can include B-cell aplasia, hypogammaglobulinemia, and infections. B cells are also central to the pathogenesis of autoimmunity, and B-cell–targeted therapies such as rituximab, which targets CD20-expressing B cells, have been used to treat autoimmunity for several years. Disease remissions occur, but subsequent flares are common. Recent trials of newer agents indicate that efficacy may reflect the depth of B-cell depletion.3 Müller et al. made these observations in an uncontrolled context in a small heterogeneous series of patients, with limited follow-up. Nonetheless, the findings are remarkable. These patients had serious multisystem disease that was refractory to at least two conventional therapies. Similar outcomes can sometimes be achieved with autologous stem-cell transplantation but with a risk of substantial toxic effects and even death.4

Two properties of CD19 CAR T cells may explain their apparent superiority over anti-CD20 monoclonal antibodies. First, CD19 is expressed more broadly than CD20, particularly on plasmablasts and a majority of plasma cells. Whereas rituximab primarily depletes B cells with some secondary loss of plasmablasts, CD19 CAR T cells have direct cytotoxicity for plasmablasts and many plasma cells. Second, CAR T cells are more potently depleting than monoclonal antibodies, probably owing to better tissue penetration and their intrinsic lethality. A key implication of the work of Müller et al. is therefore that at least some B-cell lineage–dependent autoimmunity resides beyond B cells themselves, in plasmablasts and plasma cells. This inference is consistent with current thinking; indeed, plasma cells have been identified as a critical bastion of autoimmunity.5
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https://www.nejm.org/doi/full/10.1056/NEJMe2400203
 
The sceptical response would be that we had pretty much as good results as this in our first lupus study in 2000 with rituximab. But I am very happy to hope that these remissions pan out longer.

One thing that this finally puts to rest is the view that B cell depletion was not much use for lupus and that rituximab didn't really work - based on very badly designed studies that failed to meet endpoint in lupus despite the clear benefit in RA. Our original study picked people capable of showing a clear response and they did. It was small and open label but the findings were pretty much like this CAR-T results, dramatic and lasting many months and in at leas some cases long term. It is actually much easier to get long term benefit in lupus than RA probably because lupus is a naturally relapsing and remitting disorder.

The reasons for CAR-T being better are likely right, although I am not convinced CD19 and CD20 are so different. CD20 was the right target for a monoclonal because CD19 recycles in the B cell membrane too quickly. That may not be particularly relevant for CAR-T.

The 64 thousand dollar question was always whether to get long term benefit you need to kill more B cells or long lived plasma cells. If really deep B cell depletion is crucial then CAR-T may do it and that may be an easy route to cure. If it is long lived plasma cells it will be harder work but once we know which is important developing cures should be a straightforward strategic exercise, even if hard to get safe and sure.
 
Sid said:
How do we find out? Is there any reason to suspect that ME/CFS may have something to do with long-lived plasma cells which would explain why RTX didn't work?
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Any disease of unknown cause that fails to respond to rituximab might do so because it is driven by long lived plasma cells. At present I think the chances of that for ME are slim but we know so little I would not exclude it.

If these people can show that CAR-T therapy produces long term benefit in conditions like scleroderma, that so far have proven resistant to almost everything and have antibodies that do not go away with rituximab, then a further trial in ME would be justifiable, even if I would not necessarily lobby for it.
 
I never expected that I, as a MECFS/Sjogrens/POTS/SFN person can be cured by CD19 alone, I feared for 2 yrs it will require BCMA.

Seems Chinese recognized this earlier so do more of these BCMA alone trials!

As it is already clear significant % of autoimmune illnesses and/or patients is not okay w CD19.
The problem is in USA & EU, there are no trials with BCMA, and especially no with dual.
(only Chinese Gracell in USA should be CD19-BCMA).
I heard prof. Schett saying giving both would be too much, but BCMA alone, can not reset. & Will take a lot of time to do BCMA in the West, especially with the T-cell lymphoma risks.


According to anti-smith aabs and latest tests, I have lupus too, but i even forget about it 99% of the time as this fckr POTS/SFN/Sjogrens is so stubborn stuff.

TLDR:
In other words... A graph is worth a thousand words..

From Schett's 15 case series w CD19

upload_2024-2-24_3-5-8.png
 
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EndME said:
I don't have access but from what I saw in the news reports the first patients underwent treatment in March 2021, i.e. apart from the 2 year follow-up data in the paper, the authors will soon have data reaching 3 years back..
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It will be soon 3 years for the first [German] patient (it was done 1+ years earlier in China and because they used CD19-BCMA they have even better results).

The data from Chinese researchers from January/2023. I spoke to the main researcher last weekend, who is a hematopathologist in NYC, and I am really impressed, he confirmed and showed me data/graphs this is all still valid -nobody relapsed and still, nobody has autoantibodies, so basically they have data for 4+ years now, for their first patient. And unlike with CD19 alone, they managed to get rid of all antibodies. I asked him to treat me multiple times as he previously mentioned that option, but their hospital board in China is very strict and only treated for now lupus nephritis, and a couple of other life-threatening AID cases, like ITP, so no way for me, for only QoL indication... which confirms they're really serious and by the book!

P1 and P2 maintain drug free CR and with no autoantibodies post-cCAR approximately 40 and 20 months respectively. All B cells recovered within 2-6 months with no indications of relapse. At ≥1-4 months post-treatment 9 patients were negative for, anti-dsDNA autoantibody, anti-nuclear autoantibody, anti-SSA/Ro52 autoantibody, anti-SSA/Ro60 autoantibody, anti-ribosomal P, and anti-U1-snRNP. Among 9 patients rapid improvement within 1 month after cCAR, mean SLEDAI-2K dropped from 8.7 mean at baseline to 2 at 1 month (7 patients no symptoms), and mean drop to 0.88 within 6 months (9 patients no symptoms). All patients achieved 100% response and are maintaining medication free recovery (no immunosuppressives or glucocorticoids). An immune “reset” was confirmed via flow cytometry showing that most of recurring cells are naïve B cells, and further observed in BCR deep sequencing (patients 3-4), whereby IgG and IgA clonotypes are absent and non-class-switched BCR repertoires are greater than 95% IgM heavy chain.
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The photo is from 1st German patient 1000th-day celebration in December.
I talked with her and published on this site:https://autoimmunecar.com/patients-experiences
(the site is barely started so I postpone sharing but I guess why wait... )
upload_2024-2-24_4-40-23.png
 
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Jonathan Edwards said:
Any disease of unknown cause that fails to respond to rituximab might do so because it is driven by long lived plasma cells. At present I think the chances of that for ME are slim but we know so little I would not exclude it.

If these people can show that CAR-T therapy produces long term benefit in conditions like scleroderma, that so far have proven resistant to almost everything and have antibodies that do not go away with rituximab, then a further trial in ME would be justifiable, even if I would not necessarily lobby for it.
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May I ask, why isn’t it also possible like they said in a few of the articles on this that monoclonal antibodies like rituximab just aren’t killing all the B-cells in every compartment and this CAR-T approach is more effective at that?
 
leokitten said:
May I ask, why isn’t it also possible like they said in a few of the articles on this that monoclonal antibodies like rituximab just aren’t killing all the B-cells in every compartment and this CAR-T approach is more effective at that?
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Sure, I may not have made that clear.
We know that rituximab produces a rapid fall in some autoantibodies and not others. That suggests that cutting off supply of new B cells leads to drop in antibody levels because they are produced by relatively short lived plasma cells. For other autoantibodies which do not fall this is presumably because they are produced by longer lived plasma cells.

But there is a second issue - why antibody levels come back up when B cells return, or, as in some cases, months or years later. This might be due to residual memory cells that survived but did not proliferate during the depletion period or it might be because antibody from remaining plasma cells re-educates new B cell clones into a positive feedback loop of production (which seems likely for epidemiological reasons).

What is not clear is why autoreactive memory B cells should hide away during the period of depletion and not replenish plasma cells. That could be because proliferation requires memory cells to enter follicles where they are exposed to CD57+ve killer cells. But follicles are probably rather a good place for B cells to survive because complement inhibitor levels are very high there. So it is all very unclear.

It may seem surprising that it is not possible to work out from biopsies and kinetics which is the likely mechanism for relapse. However, as for cancer, if reactivation of a cycle only requires a tiny number of cells, it may not be so surprising.
 
I was at Grand Rounds at UCL yesterday. We talked about CAR-T for scleroderma. Everything is looking rather encouraging partly because Car-T may deplete more but also because of the option of killing B cells specific for certain antigens. That is unlikely to work for rheumatoid but it could work for scleroderma because the antigen is normally hidden away in nuclei and CAR-T cells would probably only see it in follicle centres on dendritic cells next to the autoreactive B cells - exactly where you want.

What we really need next (maybe) is a strategy for using CAR-T to deplete overactive T cell populations. The method seems flexible enough to do that.
 
Jonathan Edwards said:
I was at Grand Rounds at UCL yesterday. We talked about CAR-T for scleroderma. Everything is looking rather encouraging partly because Car-T may deplete more but also because of the option of killing B cells specific for certain antigens. That is unlikely to work for rheumatoid but it could work for scleroderma because the antigen is normally hidden away in nuclei and CAR-T cells would probably only see it in follicle centres on dendritic cells next to the autoreactive B cells - exactly where you want.
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I know CAR-T aimed at B-cells for antigens of MusK and DSG3-CAART for pemphigus vugaris, failed, with or without chemo preconditioning. Do you think Sjogren's w SSA or SSB would be a good target for CAART? I think I saw study in mice for SSB, but makes no sense with a disease with so many antibodies, or?

Do you think some illnesses wouldn't relapse from BCMA because the antigen is intracellular so B-cells wouldn't get activated? I see some BCMA only studies but I am wondering what to expect, how long the remission lasts ...

there are 2 case reports with RA, 1 Schett's SLE patient and her RA is 'gone' and one is in BCMA reports on NMOSD, it says:

In addition, the patient with rheumatoid arthritis (RA, Patient 10) showed improvement in RA disease activity at 12 weeks post infusion. Disease Activity Score in 28 joints and erythrocyte sedimentation rate decreased from 4.698 (indicating an active status) to 1.987 (indicating a remission stage), and tender joint counts decreased from 24 to 0 in Patient 10.
.

What we really need next (maybe) is a strategy for using CAR-T to deplete overactive T cell populations. The method seems flexible enough to do that.
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Chinese have anti-CD7 studies but I think I was told it's absolutely reserved for super severe patients as it's way too risky?
 
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Pibee said:
I know CAR-T aimed at B-cells for antigens of MusK and DSG3-CAART for pemphigus vugaris, failed,
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Interesting. My thought would be that getting a bispecific or trispecific CAR-T to work using antigen specific ligands could require a whole developmental story in its own right. Availability could be crucial. There is also the tricky problem of epitope complementarity. In order to generate an effective B cell response you almost certainly need different clones recognising non-overlapping epitopes, even if one epitope dominates. Similar considerations may apply to CAR-T - you may need to bind particular epitopes. I am always amazed that these things actually work when they do but I think for this strategy the fine tuning may be really important.

Pibee said:
Do you think some illnesses wouldn't relapse from BCMA because the antigen is intracellular so B-cells wouldn't get activated? I see some BCMA only studies but I am wondering what to expect, how long the remission lasts ...
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I had a similar conversation in the corridor yesterday. And we got pretty muddled. This is the sort of debate that requires sending Linda out for a few bottles of chardonnay and a couple of hours in the office on a Friday evening. It could get really interesting but by email I doubt we will get very far!!

Pibee said:
Chinese have anti-CD7 studies but I think I was told it's absolutely reserved for super severe patients as it's way too risky?
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Interesting. People are always frightened of anti-T cell strategies. Yet early on Campath was given to RA patients (as was anti-CD7 in fact) and some had virtually no T cells for a decade. Despite still having RA they didn't seem to come to much harm from no T cells. Maybe CD7 is a bit broad or maybe there are some technical issues. But I think people have got a thing about this.
 
Sid said:
CD19 CAR T-Cell Therapy in Autoimmune Disease — A Case Series with Follow-up

  • Fabian Müller, M.D.,
  • Jule Taubmann, M.D.,
  • Laura Bucci, M.D.,
  • Artur Wilhelm, Ph.D.,
  • Christina Bergmann, M.D.,
  • Simon Völkl, Ph.D.,
  • Michael Aigner, Ph.D.,
  • Tobias Rothe, Ph.D.,
  • Ioanna Minopoulou, M.D.,
  • Carlo Tur, M.D.,
  • Johannes Knitza, M.D.,
  • Soraya Kharboutli, M.D.,

Abstract
BACKGROUND

Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission.

METHODS
We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology–European League against Rheumatism (ACR–EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded.

RESULTS
The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR–EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell–associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization.

CONCLUSIONS
In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.)

https://www.nejm.org/doi/full/10.1056/NEJMoa2308917
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The team from Erlangen have uploaded trial information onto clinicaltrials.gov under the title MB-CART19.1 in Refractory SLE.

clinicaltrials.gov currently lists 40 CAR-T cell therapy studies for autoimmune diseases. 24 of those are happening in China, 14 in America and 1 each in Germany and France.

The trial on clinicaltrials.gov that would have the longest follow-up data (without having been withdrawn) would the Descartes-08 trial for Generalized Myasthenia Gravis which by now has follow-up data for +4 years (newer data has been announced but not yet published and the Phase 1b study was launched in 2019), has also published first results and the enrollment for the RCT version of the trial is already underway and topline-results should be out by the end of the year (additionally a Phase 1 study with the same drug has been completed in SLE and has now moved onto Phase 2, with several other trials currently being in the preclinical stage).

What is encouraging on clinicaltrials.gov are the amount of trials that started last month or this month. It seems that there's currently a lot of initiative.
 
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CD19 Chimeric Antigen Receptor T Cell Treatment: Unraveling the Role of B Cells in Systemic Lupus Erythematosus

Abstract
B cell generation of autoantibodies is a crucial step in the pathogenesis of systemic lupus erythematosus (SLE). After their differentiation in the bone marrow, B cells populate the secondary lymphatic organs, where they undergo further maturation leading to the development of memory B cells as well as antibody-producing plasmablasts and plasma cells. Targeting B cells is an important strategy to treat autoimmune diseases such as SLE, in which B cell tolerance is disturbed and autoimmune B cells and autoantibodies emerge. This review discusses the functional aspects of antibody- and cell-based B cell–depleting therapy in SLE. It thereby particularly focuses on lessons learned from chimeric antigen receptor (CAR) T cell treatment on the role of B cells in SLE for understanding B cell pathology in SLE. CAR T cells model a deep B cell depletion and thereby allow understanding the role of aberrant B cell activation in the pathogenesis of SLE. Furthermore, the effects of B cell depletion on autoantibody production can be better described, ie, explaining the concept of different cellular sources of (auto-) antibodies in the form of short-lived plasmablasts and long-lived plasma cells, which differ in their susceptibility to B cell depletion and require different targeted therapeutic approaches. Finally, the safety of deep B cell depletion in autoimmune disease is discussed.

https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/art.42784
 
CD19-targeted chimeric antigen receptor T cell therapy in two patients with multiple sclerosis

Highlights
  • CD19 CAR-T cell therapy showed tolerable short-term safety in two patients with MS
  • CAR-T cell expansion was observed in cerebrospinal fluid without neurotoxicity
  • Intrathecal antibody production decreased after CAR-T cell infusion in one patient
Summary

Background
Progressive multiple sclerosis (MS) is characterized by compartmentalized smoldering neuroinflammation caused by the proliferation of immune cells residing in the central nervous system (CNS), including B cells. Although inflammatory activity can be prevented by immunomodulatory therapies during early disease, such therapies typically fail to halt disease progression. CD19 chimeric antigen receptor (CAR)-T cell therapies have revolutionized the field of hematologic malignancies. Although generally considered efficacious, serious adverse events associated with CAR-T cell therapies such as immune effector cell-associated neurotoxicity syndrome (ICANS) have been observed. Successful use of CD19 CAR-T cells in rheumatic diseases like systemic lupus erythematosus and neuroimmunological diseases like myasthenia gravis have recently been observed, suggesting possible application in other autoimmune diseases.

Methods
Here, we report the first individual treatment with a fully human CD19 CAR-T cell therapy (KYV-101) in two patients with progressive MS.

Findings
CD19 CAR-T cell administration resulted in acceptable safety profiles for both patients. No ICANS was observed despite detection of CD19 CAR-T cells in the cerebrospinal fluid. In case 1, intrathecal antibody production in the cerebrospinal fluid decreased notably after CAR-T cell infusion and was sustained through day 64.

Conclusions
CD19 CAR-T cell administration in progressive MS resulted in an acceptable safety profile. CAR-T cell presence and expansion were observed in the cerebrospinal fluid without clinical signs of neurotoxicity, which, along with intrathecal antibody reduction, indicates expansion-dependent effects of CAR-T cells on CD19+ target cells in the CNS. Larger clinical studies assessing CD19 CAR-T cells in MS are warranted.

https://www.cell.com/med/fulltext/S2666-6340(24)00114-4
 
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