"Scientists hail autoimmune breakthrough" - the Guardian

I don't know if this has been posted elsewhere but I thought it was very interesting. I wonder if something like this might end up being helpful for a subset of pwME...

https://www.theguardian.com/science...disease-therapy-breakthrough-car-t-cell-lupus

"In the latest work, doctors took T-cells from the lupus patients and modified them so that, on re-infusion, they attacked the patients’ B cells. In lupus, B cells churn out autoantibodies, which instead of defending the body against invading pathogens, attack healthy tissues instead.

According to the study in Nature Medicine, the therapy in effect wiped out the patients’ aberrant B cells and dramatically improved their condition. The disease affected multiple organs in all five patients, but after the therapy severe symptoms including arthritis, fatigue, fibrosis of the heart valves, and lung inflammation all cleared up."
Blood tests on the patients showed that their B cells recovered about four months after the treatment, but they no longer produced aberrant antibodies and the patients remained disease-free. Writing in the journal, the authors speculate that the therapy led to a “rebooting of the immune system”.

 

Wow.. what an exciting result.

 

Yes, it is exciting.

But remember that Leandro, Edwards et al., in around 2000, reported a similar series (actually a bigger one) of SLE patients treated with rituximab - with similar results. And in the recent series patients had to have two cytotoxic drugs in addition to the CAR T cells.

Nevertheless, if CAR T cells can kill more B cells than rituximab and really do produce sustained remission in lupus then our original hypothesis is finally confirmed and the long awaited upgrade in technology has arrived. It would mean that we do not need to chase plasma cells.

We need much more data on long term follow up though.

I hope to make use of these data for a presentation on B cell depletion treatments in ten days time.

 

Uh, would you look at that. You treat the disease, you treat the symptoms. No need for biopsychomumbojumbo. In fact it appears that the symptoms are... *drum roll*... consequences of the disease. Who knew?

 

Is it known why lupus affects far more women than men?

 

Huge if true.

 

Almost all B cell based autoimmune diseases are more common in women. Differences in antibody production between males and females make sense because women make antibodies for their newborn babies. The antibody levels are not different but I gather that recent work has shown that women produce a more vigorous antibody response to antigens they have seen recently - maybe the B cell system is more immediately reactive than in men. That might explain more mistakes. Autoimmunity is basically when the system makes an antibody by chance that manages to slip through quality control far enough to take advantage of the normal chain reaction that is used for antibodies to microbes.

The intriguing thing about lupus is that whereas most autoimmune diseases are about three ties as common in women lupus is nine times as common. That might be because the check point that fails in lupus is specifically associated with complement. There is also an interesting recent report of a lupus case with a TLR gene defect that I think was on the X chromosome so there might be an additional sex linked factor there. What is a bit odd about that is that genes on X chromosomes tend to produce diseases in men because they can be x-linked recessive since men only have one x so cannot make up the defect with the other one.

 

Huge if it pans out. The findings so far are not really different from ours in 2000. The reported follow up of three months for some of the cases is pretty short - I think we followed ours up for a least six months before reporting a result.

 

The paper offers an explanation for why rituximab doesn’t work for SLE

 

Yes, we knew about that before we started with RA in 1998. Rituximab does not clear follicular B cells. But I am not clear that we have evidence for CAR T cells doing that in these patients? As far as I know no biopsies have been done - they are very hard to justify. If CAR T cells do clear follicular B cells that may be a major development. But if plasma cells are the real problem then it won't make any long term difference. We got up to five years remission in RA but eventually the plasma cells (or residual B cells??) won.

The key thing is what happens to these patients in this CAR T cell trial over a period of five years. Do they relapse like after rituximab or not? Rituximab actually works pretty well. The reason it was never licensed for lupus is that the the trials were extremely badly designed by the drug companies. A more recent trial with a rituximab successor has shown good results.

 

None of the traditional immunosuppressives mentioned have the sort of effect B cell depletion gives (i.e. as quoted in the above post). Belimumab depletes B cells but not very powerfully. I am surprised that only one case seems to have tried rituximab but that probably reflects licensing. Belimumab got licensed because the people involved were more intelligent about trial design.

 

In the two patients with the longest follow-up, seroconversion of antinuclear antibodies was observed, indicating that abrogation of autoimmune B cell clones may lead to a more widespread correction of autoimmunity.

Seroconversion is fairly easy for anti-DNA but more difficult for other ANA. Their figures look fairly similar to what we are used to. But yes, this is what we predicted in our 1998 paper before we actually started using B cell depletion - that abrogating autoimmune clones would get rid of the problem. In fact if one didn't think that the treatment would look fairly poor risk/benefit.

What is slightly odd is the idea of 'more widespread correction of autoimmunity'. What more is there to correct if the autoimmune clones are gone? I suspect they cannot quite get themselves to abandon the old myth that there is some T cell drive behind it all. If that were the case the chances of any of this working would I think be low.

 

Elsewhere they talk about how the patients also lost other autoantibodies. I think that’s what they’re referring to, not T cells.

 

Furthermore, generalizability of the CD19-targeted CAR T cell approach to other autoimmune diseases is unclear.

Again, yes, as we have said since Maria Leandro's original findings on long lived autoantibodies, but I think they miss a trick here.

If autoimmune plasma cells are long lived the disease may still gradually fade away if you break the cycle of regeneration of auto reactive clones fed by autoantibody. I don't think these people have cottoned on to the dynamics of B cells really. The long lived plasma cells do two things. They go on making antibody, which may produce symptoms, but those antibodies may also educate new B cell clones recognising the same antigen to survive and proliferate.

The 64 thousand dollar question is whether relapse after rituximab was due to old B cell clones (hidden in follicles) getting going again or new clones being educated. If CAR T cells do better by killing follicular B cells then leaving plasma cells behind may not matter long term. If killing all follicular B cells isn't the problem then CAR T cells aren't going to be much of an advance.

 

No, the autoantibodies are made by the B cell clones they think they have killed, or at least their plasma cell offspring. So that would not be 'more widespread'. If they mean anything it must be something else. I have a suspicion that they know perfectly well that we have provided an explanation for all this but the politics don't allow them to quote it !!