Targeted depletion of TRBV9+ T cells as immunotherapy in a patient with ankylosing spondylitis, 2023, Chudakov et al

Targeted depletion of TRBV9+ T cells as immunotherapy in a patient with ankylosing spondylitis

Abstract
Autoimmunity is intrinsically driven by memory T and B cell clones inappropriately targeted at self-antigens. Selective depletion or suppression of self-reactive T cells remains a holy grail of autoimmune therapy, but disease-associated T cell receptors (TCRs) and cognate antigenic epitopes remained elusive.

A TRBV9-containing CD8+ TCR motif was recently associated with the pathogenesis of ankylosing spondylitis, psoriatic arthritis and acute anterior uveitis, and cognate HLA-B*27-presented epitopes were identified. Following successful testing in nonhuman primate models, here we report human TRBV9+ T cell elimination in ankylosing spondylitis. The patient achieved remission within 3 months and ceased anti-TNF therapy after 5 years of continuous use. Complete remission has now persisted for 4 years, with three doses of anti-TRBV9 administered per year. We also observed a profound improvement in spinal mobility metrics and the Bath Ankylosing Spondylitis Metrology Index (BASMI). This represents a possibly curative therapy of an autoimmune disease via selective depletion of a TRBV-defined group of T cells.

The anti-TRBV9 therapy could potentially be applicable to other HLA-B*27-associated spondyloarthropathies. Such targeted elimination of the underlying cause of the disease without systemic immunosuppression could offer a new generation of safe and efficient therapies for autoimmunity.

https://www.nature.com/articles/s41591-023-02613-z

 

Posted because it seemed "fancy" to a layman like me. It doesn't have any relevance to ME/CFS as far as I can tell (quite the opposite).

Ankylosing spondylitis is an inflammatory T cell disease and is majorly driven by genetics. In fact the association to HLA-B27 is so strong that it’s even part of the diagnostic criteria. The male to female ratio is 3:1.

In the above trial the T-cells of the patients expressing TRBV9 were selectively depleted using an anti-TRBV9 monoclonal antibody (BCD-180) and the patient went into remission. He relapsed after treatment with TRBV9 T-cells reappearing. Subsequently the patient responded to an additional course of treatment, which has been continued.

After treatment of this patient, a large phase 2 study with this drug has started two years ago in Russia https://clinicaltrials.gov/study/NCT05445076, thus data should be available shortly. Allegedly a phase 3 study is already being planned.

Motivated by their work on self and bacterial peptides, the authors seem to be very much focused on autoreactive T-cells. From what I can tell the treatment would work just as well if the T-cells were not autoreactive and I'm not sure if autoreactivity is an important part of their story.

 

I very much agree. But I think this could be relevant to ME, for reasons I have discussed on the forum but maybe 5 years ago now so worth refreshing perhaps.

When I left rheumatology in 2010 I had been trying to persuade people for about 10 years to use an anti-CD8 Map on ank spond. The attitude I met was that it would be too risky in infection terms. I could not see why particularly.

This sounds a very interesting study. I was unaware of a link to specific TCR motif. If selective depletion of cells carrying that motif works it would be very impressive.

I agree that this may not be an autoreactive motif. It might turn out to be a motif involved in some idiosyncratic 'innate style' CD8 response maybe involved in removing cells bearing post-translationally modified material indicative of local danger.

My speculation about psoriasis, Reiter's and Crohn's and ank spond (all linked to MHC Class I, suggesting CD8 or NK crytotoxic cell elevance) is that the four diseases represent the four T cell traffic domains: skin, mucosae, gut, elsewhere. (Localisation in ank spond can be explained by TGFbeta distribution on tissue matrix, but that is a more complicated part of the story.) They may simply be what it looks like for CD8 cells to be 'too enthusiastic' in each domain.

When I first started thinking about ME I wondered if perhaps it might be the post-infective result of over-enthusiasm in a fifth domain - which we might call stay-at-home. There might be CD8 T cells that express none of the domain specific adhesion molecules and rather than police specific peripheral tissues police lymphoid tissue itself. Policing lymphoid tissue is a major job of its own, because CD8 cells are used there to refine clonal selection for B cells and very likely CD4 T cells.

You could then have an illness with systemic symptoms similar to Crohn's or Reiter's, including 'fatigue' but with no local inflammation. Symptoms would be mediated by non-inflammatory danger signals, possibly through T cell/neural interaction through muscarinic receptors etc. I don't know if I buy that as at all likely but it remains in my view a sort of model for how a theory could fall into place for ME.

If the 'seronegative' auto inflammatory diseases (above) can be controlled then it might be worth trying something similar for ME. You might need to use a broader CD8 target though.

The only worry I have is that the opening the abstract suggests not very clear thinking - as you point out. And it may turn out that the data are not all they seem to be- but I would give the benefit of the doubt here.

 

So if this was a common cause of ME/CFS the would you expect to see a signal in DecodeME (GWAS study*) and would it be?
Also, re study of families with more than 1 member affected* - looking for rare variants - would you expect to see a signal and would it be?

EDIT - any news re Ron Davis's NIH funded HLA study? It was due to be completed a year ago.

*compare common genetic variants in large numbers of affected cases

 

What do you mean by this? Thanks.

 

I found this very interesting - thanks for laying it out so clearly. Do you have thoughts on what an initial/small study could look like to test this idea?

 

Maybe just an anti-CD8 antibody to reduce CD8 activity generally.
It would be interesting to know what has been established about the specificity of the anti TRBV9. Maybe it isn't as specific as they hope and is more broadly anti TCR.

 

You might but might not. A T cell overenthusisam mechanism could be tripped stochastically by anything and not have a genetic link. Itmight, but then again it could be a regulatory sensitivity factor other than HLA. Examples are complement gene links in lupus, which are still in MHC, but not HLA, and PTPN22 in RA, which is outside MHC.

 

A trial of anti-CD8might be the simplest option. If it did nothing with CD8 depletion the idea would be refuted fairly effectively.

DecodeME is the other way, to pick up genetic link leads to threshold effects - so let's see.

 

Thank you very much for your responses - any suggestion re delivering that trial e.g. a Jonathan Edwards type Medical Doctor---drug company --?

 

Have anti-CD8 antibodies been used on live humans other than the TRBV one above?

 

I don't know. I suspect that drug companies had cold feet and no independent academics have had the sense to give it a go.

 

snow leopard posted on Twitter/X-
"I'm not so sure about this for ME. I would like to see a trial of anti-CD8 in the AIDP subset of GBS patients though."

 

Link please—thanks.

 

EDIT - I recall e.g. Vicky Whittemore (NIH) in one of the recent ME/CFS Roadmap talks responding to a question re drug trial - from memory the response was roughly "insufficient evidence" - which I agreed with. However, this looks like a situation where a drug trial could reasonably be done now - reason to expect it's relevant to ME/CFS - would test that hypothesis (as per rituximab trial) and a trial may be the only way to test relevance --- possibly DecodeME may turn up evidence re relevance.
I thought those tagged might be able to highlight the opportunity but the obvious "miss" was NIH but I doubt they are likely to run a trial?
@Jonathan Edwards


https://twitter.com/user/status/1755714440211615910

 

Don’t need an efficacy trial—need maybe a 2-3 patient safety trial for anti CD8 MAB. Maybe 1 HC and 2 MECFS patients. Only for safety data—as far as I know no humans have been injected with a general anti CD 8 mab.

 

I agree that if anti-DC8 has not been given to humans yet a safety focused trial is in order. But I would expect it to be possible to do a primate trial either of the same antibody or something expected to have significant depleting efficacy for the primate species.

If depleting CD8 is safe in primates then I think it is reasonable to test safety in a small human trial, but monitoring for signs of efficacy as well. If I were setting it up I would try to include some continuous altimeter monitoring. If the antibody actually worked I would hope to see at least three patients show a major increase of activity all with a similar time profile (but without making any prediction or even suggestion of what that time profile might be).

I don't think there is any need to treat healthy controls. I cannot see it as ethical to try a drug on healthy people just in case it kills people, when the volunteers have nothing to gain. I never really understood the use of healthy controls for most drugs.

Also, rather than go for 2-3 patients I would think of treating up to ten in a spaced out series - maybe one per month. The reason for that is the disaster that occurred with a cytokine trial where six openly were given drug all together and several either died or nearly.

I think the tweet is fair enough but to say that I suggested a trial is potentially misleading. I suggested that a trial might be good idea. I am not suggesting anyone does one without very careful analysis of the available evidence bearing on safety.

 

Apologies - perhaps it would help to clarify if I posted this* --- don't think you can delete tweets?

*"to say that I suggested a trial is potentially misleading. I suggested that a trial might be good idea. I am not suggesting anyone does one without very careful analysis of the available evidence bearing on safety."

 

No, it is fine. As long as I know it isn't going to go into a viral spiral!! Which I know it won't.