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

No I have a dentist appointment that day.
The only person speaking who understands B cells is my second in command Maria Leandro from 2000 days. The others are just local people wanting to be seen to be in on the B cell act.
If I want to know what is going on I can ask Maria or Pedro.

 

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 ?

 

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 ?


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

 

"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.

 

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

‘Exciting’ new lupus treatment could end need for lifelong medication

 

where was this private clinic ??