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

Maria Leandro's talk is the one I'd be most curious about, too. How do I choose between CAR and bispecific?
 
Jonathan Edwards, what do you think about the results from the teclistamab CD3-BCMA bispecific recently published like SLE case report (NEJM paper link) and pSS, IIM, RA and SSc (all had ILD). Do you think it could "reset" B cells memory in the same way as CAR-T (hopefully) does?
It seems that in these reports it only happened or looks promising in SLE and SSc case (perhaps RA too?). But they've got only 1-2 month's worth dose overall, and the follow up time is so short.
It seems to me SLE case maybe just got lucky like the early rituximab results you mentioned? But then again, you said some have 5 year remission from RTX too?!

this is not looking so promising to me, but longer treatment might change a lot ?
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but then again this is from CAR-T BCMA-CD19, the drop of SSA-ro60 (ro52 graph looks very similar) is so slow here too.. . Why? are these LLPC so hard to reach and kill? (around 90 days B cells came back ) teclistamab is only 16 weeks follow up, perhaps the same might happen

is it possible these autoantibodies are produced within salivary glands and bispecifics penetrate there less than to BM ?
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EDIT: just found this for SLE patient, says almost 6 months in remission, so she didnt relapse. (as the report is 16 weeks)
The autoimmune disease left the 23-year-old dependent on a wheelchair. Today - almost six months after starting treatment - the patient is completely free of symptoms. Therapy began in March, and the data from an observation period of 16 weeks have now been published.https://idw-online.de/en/news839150
 
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Also World-first therapy using donor cells sends autoimmune diseases into remission

The treatment’s success in three people raises hopes for mass production of cutting-edge CAR T therapies.

One woman and two men with severe autoimmune conditions have gone into remission after being treated with bioengineered and CRISPR-modified immune cells. The three individuals from China are the first people with autoimmune disorders to be treated with engineered immune cells created from donor cells, rather than ones collected from their own bodies. This advance is the first step towards mass production of such therapies.

One of the recipients, Mr Gong, a 57-year-old man from Shanghai, has systemic sclerosis, which affects connective tissue and can result in skin stiffening and organ damage. He says that three days after receiving the therapy, he felt his skin loosen and he could start moving his fingers and opening his mouth again. Two weeks later, he returned to his office job. “I feel very good,” he says, more than a year after receiving the treatment.
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Referencing —

Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis (2024)
Xiaobing Wang; Xin Wu; Binghe Tan; Liang Zhu; Yi Zhang; Li Lin; Yi Xiao; An Sun; Xinyi Wan; Shiyuan Liu; Yanfang Liu; Na Ta; Hang Zhang; Jialin Song; Ting Li; Ling Zhou; Jian Yin; Lingying Ye; Hongjuan Lu; Jinwei Hong; Hui Cheng; Ping Wang; Weiqing Li; Jianfeng Chen; Jin Zhang; Jing Luo; Miaozhen Huang; Lehang Guo; Xiaoming Pan; Yi Jin; Wenjing Ye; Lie Dai; Jian Zhu; Lingyun Sun; Biao Zheng; Dali Li; Yanran He; Mingyao Liu; Huaxiang Wu; Bing Du; Huji Xu

Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.


Link | PDF (Cell)
 
"One of the recipients, Mr Gong, a 57-year-old man from Shanghai, has systemic sclerosis, which affects connective tissue and can result in skin stiffening and organ damage. He says that three days after receiving the therapy, he felt his skin loosen and he could start moving his fingers and opening his mouth again. "

This is implausible to the point of serious concern. In advanced scleroderma the tissues are permanently fibrotic and also devascularised. There is no reason to think that significant improvement could occur in less than a matter of many weeks and there are good reasons to think that they can never occur. The vascular drop out strongly suggests that repeated damage has ended in telomere exhaustion so that recovery is essentially impossible.

Moreover, killing CD19 positive cells would not be expected to have any local effects on tissue until daughter plasma cells producing antibody had died. Which is why with any form of B cell depletion benefit tends to be delayed by several months.

In early scerloderma there is oedema in the tissues, which can respond to steroids. The most likely explanation I can think of for an improvement in 3 days is that the patient had some steroid as part of the protocol.

Beyond that, assessment of benefit from any B cell depletion therapy is only meaningful at two years follow up, because relapse occurs either at 6 months or around 1-2 years in most cases.

I am wondering what the advantages or disadvantages of allogeneic cells might be? Presumably off the shelf vs rejection events. I don't know much about the survival kinetics for CAR-T but one would want to get rid of them at some point to allow B cells to return.
 
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I had the same thought regarding reversal of fibrosis, which I would have assumed was essentially immutable once established. I've grabbed the paper so will quote the relevant parts, as opposed to the lay presentation. I note the temporary decrease in autoantibody levels for one of the patients.

For dcSSc, the clinical improvement from the baseline was primarily evaluated using the American College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS) score, which includes the modified Rodnan skin score (mRSS), forced vital capacity (FVC), HAQ-DI, PGA score, and PtGA score. An ACR-CRISS score ≥ 0.6 is considered an improvement, while a score < 0.6 indicates no improvement. The response to TyU19 intervention was primarily assessed using the ACRCRISS. Patient S0102 reached an ACR-CRISS score of 0.998 at M2, 1.0 at M3, and 0.999 at M6. Patient S0103 achieved an ACR-CRISS score of 0.996 at M1, which increased to 0.999 at M2 and remained the same at M3 and M6. Using the revised CRISS assessment, patient S0103 demonstrated improvement of at least 25%, 50%, and 75% in three or more of the five core items at both M3 and M6 follow-up visits. Conversely, patient S0102, initially presenting with severe illness, exhibited improvement of at least 25% and 50% in three or more of the five core items at both M3 and M6. Following treatment, there was a significant decrease in anti-Scl-70 autoantibody levels in both patients, with near-complete elimination achieved in patient S0103 by M6. The components of ACR-CRISS, mRSS, PGA, and PtGA were significantly lower at M6 when compared with the scores at the baseline in both patients. Although patient S0102 experienced only a temporary decrease in anti-Scl-70 autoantibody levels, improvement was noted in most other clinical measurements.
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The mRSS scores for S0102 decreased from 26 at baseline to 22 at M1, 4 by M3, and 6 by M6. For S0103, whose skin hardening was prominent and rapidly progressing, the scores decreased from an initial high of 39 to 26 at M1, and further decreased to 20 at M3 and 19 at M6. Skin elasticity was further measured by wave elastography, and the elastographic color map from skin elastography revealed a transition from predominantly hard (red) tissue to softer (blue) tissue, indicating reduced stiffness. At M1 the elasticity of skin on the thighs was normal in both patients. Additionally, skin biopsies were obtained from the lateral side of the right forearm at baseline and again 6 months post treatment. Pathological morphology of the skin showed gradual improvement after treatment, as evidenced by multi-color immunofluorescence histochemistry. Specifically, patient S0102, initially presenting with follicular atrophy and a limited number of sudoriferous glands, exhibited significant hair follicle regeneration and gland rejuvenation during the 6-month follow-up. Furthermore, a decrease in transforming growth factor-beta (TGF-b) levels in the dermis of the forearm skin was also observed after intervention with TyU19. The immunohistochemistry further demonstrated that B cells were eliminated from the skin in both cases at the 3-month follow-up and remained negative in the skin at the 6-month follow-up even after the recovery of normal peripheral B cell levels.
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Interestingly they then go on to document improvement in lung fibrosis —

The severity of interstitial lung disease (ILD) was assessed by chest computed tomography (CT) scans, lung function test, and serum concentration of KL-6. For patient S0102, axial and coronal chest high-resolution CT (HRCT) scans revealed multiple patchy and linear opacities in both lungs, accompanied by thickened interlobular septa. The bilateral pulmonary inflammation, interlobar effusion, and fibrous strands were markedly reduced by the M1 follow-up and significantly improved by the M3 follow-up, which was largely maintained by the M6 follow-up.
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Although the functional improvement in the lung was mild by FVC measurement, patient S0102 experienced drastic decrease in KL-6 from 605 U/mL at baseline to the normal level of 203 U/mL at M3, which was maintained at 204 U/mL at M6, indicating significant improvement in fibrotic lung lesions. Patient S0103 had much lower lung involvement than patient S0102. HRCT scan showed fibrous linear opacities in the posterior basal segment of the right lower lobe and ground-glass opacities within the alveoli of the right upper lobe, which was largely resolved by the M3 follow-up and was largely maintained at the M6 follow-up. Functional measurement by FVC and levels of fibrotic lesion marker KL-6 in S0103 were mostly within the normal range.
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And cardiac involvement —

Cardiac lesions were measured by cardiac magnetic resonance (CMR). In S0102, at the baseline, there was extensive edema and fibrosis in the heart, especially in the left ventricular wall revealed by T2-weighted inversion-recovery imaging and late gadolinium enhancement (LGE). Significant edema absorption was observed at M1 (T2 ratio decreased from 2.1 to 1.5), and the LGE was almost fully resolved, accompanied by a decrease in naive T1 values in the affected area. Myocardial T1 mapping across various segments was conducted, and the resulting values were represented as bull’s-eye plots. A general decrease in these values was observed. All these effects persisting until M6. In patient S0103, baseline CMR images revealed less severe heart involvement compared with S0102, without obvious LGE. An elevated native T1 and T2 values in the left ventricular lateral wall (focal T1 = 1,265 ms, focal T2 = 55 ms; compared with normal cutoff values: T1 % 1,140 ms, T2 % 54 ms), suggesting acute myocardial injury. At M6 follow-up, there was a significant reduction in the native T1 values of the left ventricular lateral wall (1,229 ms). After TyU19 intervention, he also showed reduced T1 mapping values across all myocardial segments, suggesting diminished cardiac fibrosis.
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Here are the lungs. At baseline I don't think this is the worst fibrotic change you might see, eg with established honeycombing. But definitely resolving ground glass opacity and subpleural bands with traction bronchiectasis. S0103 at month 6 looks pristine at this resolution.

Screenshot 2024-10-06 at 9.49.25 PM copy.jpg
 
Re treatment protocol, steroids were tapered during pre-conditioning, then cyclophosphamide during conditioning —

Therapy and follow-up

1) Preconditioning strategy: Prior to the administration of the TyU19 infusion, all immunosuppressive medications were discontinued, except for glucocorticoids, which were tapered to a dose deemed appropriate by the treating physicians.

2) Conditioning regimen: Patients received 25 mg/m2 /day Fludarabine (FLU) from day -5 to day -3, and 300 mg/m2 /day Cyclophosphamide (CTX) on days -5 and -4.

3) Patients received an intravenous infusion of CAR T cells at a dose of 1310 6 cells/kg on D0.

4) Post-therapy cell proliferation was examined on D0, D2, D4, D7±1d, D10±2d, D14±2d, D21±2d, D30±3d, M2±3d, M3±3d, M6±7d, M9±7d, M12±7d.

5) Clinical outcomes were methodically evaluated at specific intervals: baseline, Day 14 ± 2 days, Day 21 ± 2 days, Day 30 ± 3 days, Month 2 ± 3 days, Month 3 ± 3 days, Month 6 ± 7 days, Month 9 ± 7 days, and Month 12 ± 7 days, accompanied by thorough monitoring for potential adverse events.
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The chest x-rays look better, but that might not be too surprising if active inflammatory change resolved (for whatever reason).

The skin scoring just looks like obfuscation to me. A simple measure like fist closure would be much more convincing - with a photo. If the patients could hide their nails then I would be impressed.

It says B cells were eliminated from skin, but were there any there before - we don't seem to be told. B cells are extremely unusual in inflammatory lesions unless they are in follicular structures, which occur in rheumatoid synovial but not scleroderma skin. Plasma cells occur in inflammatory lesions but from the extensive studies we did in the 1990s on rheumatoid tissues I would be extremely surprised if B cells survived in scleroderma skin. Outside follicles in RA they are extremely sparse and show fragmentation. B cells only appear to survive in tissues if in contact with VCAM-1 positive/CD55 positive stromal cells, which are present in bone marrow and lymphoid follicles. Interestingly, although synovial intimal cells are also normally VCAM-1/CD55+ they appear to be lethal to B cells, maybe because of secreted hyaluronan.

I am quite happy to believe that CAR-T therapy can halt scleroderma. I suspect it could. But 'methinks the authors do protest too much' about early resolution of significance.
 
‘Exciting’ new lupus treatment could end need for lifelong medication
Doctors are hailing a “groundbreaking” new treatment for lupus that genetically modifies a patient’s cells to fight the autoimmune disease and could end the need for lifelong medication.

Lupus can range from mild to severe, with symptoms including joint pain, skin problems, fatigue and inflammation of major organs. Patients often have to take drugs their whole lives, ranging from ibuprofen to steroid tablets and injections, or other immunosuppressant or biological medicines.

About 5 million people worldwide are thought to have the condition, which mostly affects women.

In the UK, three patients have received CAR T-cell therapy for the most serious form of lupus, which can be life-threatening and cause damage to the heart, lungs, brain and kidneys. In Germany, patients who have had the new treatment are now in remission and do not need to take lupus drugs.

Prof Ben Parker, a consultant rheumatologist at Manchester Royal Infirmary, said he believed the breakthrough could revolutionise treatment for lupus patients, and might lead to a cure for the disease.

“Lupus is a disease that requires lifelong medication, but this therapy has the potential to change that, which is incredibly exciting. This groundbreaking new therapy marks a significant milestone in our research into lupus.”

Until now, CAR T-cell therapy has mostly been used in cancer patients, but researchers believe it could treat a range of other diseases.
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‘Exciting’ new lupus treatment could end need for lifelong medication
 
siobhanfirestone said:
I know a patient who has significantly disabled with Long COVID, and for a while was focused on MAID. Awful situation. She is lucky and has wealthy family, she got CAR-T in a private clinic and is now in remission.
I think its clear there is a sub-set of patients with ME and LC that have some form of b cell mediated illness, and that we simply cant have dangerous meds like cyclo and ritux (ritux not even really working), potentially daratumumab is on the horizon as well but im sure if we even see efficacy in ME and LC patients it wont be close to the levels of what CAR-T can do.
As a brit who is currently having to pay out of pocket for immune-based medication so I can function, i really hope the NHS listens to these results, and starts trials for known autoimmune diseases and eventually ME/LC.
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where was this private clinic ??
 
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