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

Jonathan Edwards said:
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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do you have any good sources on bort and plasma cells in autoimmunity you could share specifically perchance? im not finding much online in terms of it being a part of a regieme that effects plasma cells that are not cancerous
 
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New CAR-T case report from China, this time in a patient with Sjögren's and lymphoma.

Anti-CD19 chimeric antigen receptor (CAR)-T cells not only target CD19-positive malignant lymphoma cells but also normal B cells. The utility of CAR-T cell therapy has been reported in rheumatoid arthritis and systemic lupus erythematosus; however, its use in Sjögren’s disease (SjD) remains unknown. In this study, we describe the case of a 76-year-old woman with active SjD for 10 years who was diagnosed with diffuse large B-cell lymphoma. After receiving anti-CD19 CAR-T cell therapy, she achieved complete remission (CR) on day 28. Since the onset of her 10-year history with SjD, she was negative for antinuclear antibodies and anti-Ro-52 for the first time on day 90 after CAR-T cell therapy. Six months after CAR-T cell therapy, the CR status was maintained, serum cytokine levels returned to their normal levels, and dry mouth symptoms improved. The EULAR Sjögren’s Syndrome Disease Activity Index score decreased from 5 to 2, indicating a partial remission of SjD activity compared with that before CAR-T cell treatment. In the early stage of treatment, she presented with grade 2 cytokine release syndrome and grade 1 neurotoxicity, which were completely controlled after an active intervention. This case highlights the potential application of CAR-T cells in treating autoimmune diseases, such as SjD.
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https://www.frontiersin.org/articles/10.3389/fimmu.2023.1298815/full
 
Sean said:
It is, in principle at least, amenable to more objective measures
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I think it is very difficult.

The only thing specific to SJogren's isdryndss of eyes and mouth. You can do a Schirmer test for eyes and a salivary flow test for the mouth but in most cases it is likely that the gland changes are fairly irreversible. So a treatment that abolished the immunopathology might show nothing on these.

A drop in anti-Ro is reliably measurable if you are careful with controls in the assay. But the issue is really whether Ro goes away long term - that is just a matter of waiting to see. So in the long term the effectiveness can be assessed but the clinical measuring is hard.

Sjogren's is sai to include all sorts of other things like neuropathy and indeed fatigue but the problem with those is that they often occur in the context of several autoantibodies and an overlap with lupus. Sjogren's also occurs in rheumatoid patients through a different mechanism without anti-Ro, which further confuses things.
 
"Can autoimmune diseases be cured? Scientists see hope at last."

I saw hope in 2000 when I presented the first results on B cell targeting, and was happy to say so to TV stations that had got wind of it. The American College of Rheumatology very nearly threw me out for what they thought was dangerous bullshit. Fortunately, they consulted a British colleague first who said 'If Jo thinks a cure is possible, he is as likely to be right as anyone'. So they came to me with their tails between their legs. It was rather a nice moment!
 
A lot of non-human animal experiments, which tell us little or nothing about humans.

I wonder if he's just seeking funding for further research?

"Santamaria suggests that many past failures stem from a poor understanding of the underlying mechanisms. “I think they fail because they’re going to into clinical testing before we actually know what the hell we’re doing,” he says. Now, 18 years into his research on navacims, he thinks that his team has a good shot at success.

Konig favours approaches that involve B-cell depletion. That’s the strategy that his team is working on, so he accepts that he might be biased. “The beauty is that eventually we’ll learn from the data what the right approach is.”"

There are the usual references to being "on the cusp" of developing therapies. No one can know this.
 
CAR-NK CD19 is being tested in China for Sjogrens so hopefully they release case reports early. SLE case reports look good but they released them within 15 days so no antibodies data, just SLEDAI Scores that dramatically dropped.
Big advantage over CAR-T is much lower toxicity (I read it's given outpatiently), much lower cost, no risk of turning into T-cell lymphoma... no apheresis (donor umbilical cord-derived NK cells), they don't persist very long (weeks), which is a safety advantage
Cons: possibly not enough to fully reset B memory cells (we still hope though!), might need 2-3 infusions in several weeks (they gave 2 for SLE), because as mentioned they don't persist or clone well, I've seen they're giving 100x higher dose than with CAR-T to compensate for this. Also, nobody is yet testing CD19+BCMA, I've heard a researcher said they are applying for dual for SLE, but likely nothing started yet.

I think we'll know if it works as well in the next few months
 
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Jonathan Edwards said:
It is encouraging, but measuring Sjögren's syndrome is a pretty soft thing. An improvement in dry mouth is pretty subjective, as it is for eyes. A drop in antibodies is good but to be interesting one would want to see it still low at two years.
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There are actually 2 case reports in CAR-T BCMA research on NMOSD, 3 out of 13 patients had also Sjogren's (or better say Sjogren's caused their NMOSD).

Patient 9 was 37, patient 10 was 67 years old (i guess relevant for ability to recover)

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https://www.pnas.org/doi/pdf/10.1073/pnas.2315990121

25 year old patient with Sjogrens / immune-mediated necrotizing myopathy (IMNM) successfully treated with anti-BCMA CAR-T therapy (IASO Bio, China). Follow up: 18 months

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Good to see long-term follow-up and this dramatic clinical improvement from a bedridden state and unable to lift his arms above his head to:

By the third month, he showed improvements in upper limb strength (no limitations to lift his arms) and lower limb strength with the regained ability to walk. At the 9-mo follow-up, he exhibited a near-normal neurological examination, with only a mild residual weakness (grade 4 MRC score) in proximal lower extremity muscles, and normal strength (grade 5 MRC score) in the neck, distal lower extremity, and all upper extremity muscles. He was able to get up from the floor and walk without assistance (Manual Muscle Testing-8 score from 96 at baseline to 137 at the last visit, Fig. 1F). The levels of serum CK declined from 4,778 before treatment to 260 IU/L after 18 mo, and myoglobin level decreased from 837 to 66.2 ng/mL (Fig. 1G). Arm and thigh MRI at the 18-mo follow-up demon strated reduced active muscle lesions of enhanced T1 signal (Fig. 1H). The clinical and radiographic improvement have per sisted up to the data cut-off of September 12, 2023 (over 18 mo), without any additional immunomodulatory treatments or steroid administration.
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yeah very impressive. Just afraid if anti-BCMA would make relapse earlier than when also CD19 used, and if we need both
 
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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
 
SHORT- AND LONG-TERM EFFICACY
After CD19 CAR T-cell administration, patients were regularly monitored for their disease activity. All eight patients with SLE met LLDAS criteria and had DORIS remission after 6 months (Figure 1A). Their SLEDAI-2K score was equal to zero after 6 months. Analysis of BILAG status at baseline and follow-up showed resolution of SLE in all major disease categories after 6 months (Fig. S4). Long-term follow-up of up to 29 months showed that SLE disease activity remained absent in all eight patients (SLEDAI-2K score, 0) (Figure 1B). Furthermore, anti-dsDNA antibodies disappeared and remained negative, complement factor C3 levels normalized, and proteinuria disappeared during the entire observation period. Patient 4 with SLE, who had a rebound of proteinuria 4 months after CAR T-cell therapy and in whom follow-up renal biopsy did not reveal any histopathological signs of lupus nephritis (but concomitant podocytopathy14), did not have a relapse and had only very mild proteinuria at the last follow-up (24 months).
 
Looks like the B cells came back but the disease causing antibodies did not:

ANALYSIS OF ANTIBODY REPERTOIRE
Analysis of autoantibody repertoire in patients with SLE showed seroconversion of antibodies against dsDNA, single-stranded DNA, secondary necrotic cells, nucleosomes, and Smith protein (Figure 2A). Long-term analysis of autoantibodies in patients with SLE with at least 1 year of follow-up (seven of eight patients) confirmed a sustained absence of SLE-specific autoantibodies (Fig. S5A). Assessment of antinuclear and anti-Ro60 antibodies is shown in Figure 2B, and detailed analysis of disease-associated autoantibodies in patients with idiopathic inflammatory myositis or systemic sclerosis is shown in Figure 2C.


ANALYSIS OF B-CELL PHENOTYPE
Analysis of B-cell subsets was performed at baseline, 4 months, and 12 months after CAR T-cell therapy. Gating strategies for B cells in fluorescence-activated cell-sorting analyses are shown in Figure S6. Reconstituted B cells at 4 and 12 months showed a naive B-cell phenotype, whereas CD19+CD27+ memory B cells were drastically reduced (Figure 3A). There was a limited increase in CD19+CD27+ memory B cells between 4 and 12 months, which was predominantly seen in preswitched IgD+ CD27+ B cells. CD27+CD38+ plasmablasts and SLE-associated activated CD11c+ memory B cells were not found after B-cell reconstitution. Immature CD38+ B cells, indicating reconstitution of B cells from the bone marrow, increased at 4 months and decreased thereafter. Similar results were seen in patients with idiopathic inflammatory myositis and systemic sclerosis, although depletion of memory B cells appeared to be not as deep as in patients with SLE at 4 and 12 months (Figure 3B and 3C). Details of single-cell sequencing–based analysis of immunoglobulin heavy and light chains are shown in the Supplementary Appendix, including Figures S7 and S8.
 
Discussion
These data provide evidence for the feasibility, preliminary efficacy, and side-effect profile of CD19 CAR T-cell therapy in patients with severe autoimmune disease. Despite differences in disease entities and previous treatments, the dynamics of CAR T-cell expansion and of B-cell ablation were highly consistent among patients. CD19 CAR T-cell therapy was effective independent of previous B-cell targeting by monoclonal antibodies. Because B-cell targeting by monoclonal antibodies is not approved as treatment for SLE, idiopathic inflammatory myositis, and systemic sclerosis, previous exposure to such agents was not a prerequisite for treatment. In patients with SLE and idiopathic inflammatory myositis, complete resolution of disease symptoms was observed, whereas patients with systemic sclerosis showed reduced severity of skin and lung disease. It is notable that all the patients could successfully stop their immunosuppressive medication without having relapses or worsening of their disease.

Given that patients had full B-cell reconstitution for up to 2 years without having relapses, it seems that a single injection of CD19 CAR T-cell therapy can lead to a long-lasting remission. This stable remission state is also supported by the sustained diminution of autoantibodies, which usually precede disease onset in autoimmune disease.27 In addition, the appearance of a naive non–class-switched B-cell system, the disappearance of circulating plasmablasts, and the down-regulation of specific disease-associated heavy and light chains support the concept that CD19 CAR T-cell therapy may have induced a reset of pathologic autoimmunity in these patients. Hence, although CAR T-cell therapy is directed to both pathogenic and nonpathogenic B cells, the rebooting of the B-cell system after the disappearance of CAR T cells obviously occurs in the absence of the pathogenic B cells that trigger autoantibody production.
 
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