Is it time for T cell targeting clinical trials in ME/CFS?

[V.R.T.]

I asked this question in the BTN2A1/2 thread but don't want to keep clogging that thread up. So ill quote some of the things I said there here:

So what kind of experiments could get us from this point to a point where we understand more specifics about a potential gdT cell mechinism?



Also, if the issue is BTN2A1 mediated T cell pathology, could this kind of monoclonal antibody be a potential drug? I can only see it being used in lab experiments so I assume there isn't an approved drug form yet.

Again, the gdT conundrum and the broader T cell hypothesis all seems quite similar to the B cell/autoantibody situation, where there are a lot of theories and a lot of things that you'd expect to see that we don't, and a lot of possibilities that would be hard to prove through the basic science.

With the B cells there has been ritux, dara, cyclo and there will be isa and uplinza soon. It seems like there should be equivalent trials exploring T cell hypotheses...

Absolutely!

There does seem to be a lot of evidence and hypothesising possibly implicating various kinds of T cells and yet we've had no T cell clinical trials, and a good few B cell/antibody ones, and I'm not sure the evidence for B cells is any stronger than T cells.

Are there any physician researchers who would have experience giving T cell drugs in the way Fluge and Mella have for B cell drugs?

In a manner analogous to ritux/dara for a general and specific approach to B cells and then LLPCs, perhaps there could be a pilot looking at something like Campath that is more general and another looking at the monoclonal that specifically targets gamma delta T cells.

Would such a study struggle to get funded now? If so, what would convince funders? Would pharma companies be on board? etc

Perhaps it is still a little early for this, perhaps not, but I thought it might be good to discuss if it is time and what these trials might look like. Even if it isn't, if and when more evidence comes from the genetics or elsewhere, we can have an idea of what well designed T cell drug trials would look like, what the pitfalls and dangers might be, and who we would want running them.

 

[Jonathan Edwards]

I would support a trial recruiting a small number of severe/very severe cases who fully understood the implications. Campath treatment turned out not to have very major long term adverse effects, despite depleting T cells for years. It would make sense to use a broad T depleter first I think.

 

[V.R.T.]

I would support a trial recruiting a small number of severe/very severe cases who fully understood the implications. Campath treatment turned out not to have very major long term adverse effects, despite depleting T cells for years. It would make sense to use a broad T depleter first I think.

I think focusing on severe/very severe here is a good idea. What are the implications that potential trial participants should understand?

And if we are focussing on severe and very severe, can campath be administered in a home setting?

 

[leokitten]

ITK inhibition would be a great empirical trial. E.g. soquelitinib https://corvuspharma.gcs-web.com/static-files/d08944b1-c877-4b37-ba42-578d9ed74bff

Much safer and easier to test than something like Campath

 

[Utsikt]

Perhaps starting with the severe instead of very severe, because long term adverse events for the very severe might be unliveable.

 

[V.R.T.]

Perhaps starting with the severe instead of very severe, because long term adverse events for the very severe might be unliveable.

This is a good point, although I would argue that depending on what the ADE is it might be the same for both.

 

[V.R.T.]

Are there any physician researchers in the ME/CFS field now who could conceivably take a trial like this on?

 

[V.R.T.]

It would make sense to use a broad T depleter first I think.

Is it concievable that if there is a gdT cell pathology, Campath might not be effective but the gdT monoclonal might?

Or a similar situation for any specific T cell subset?

Or is it the case that if Campath doesn't work all those hypotheses are bust?

 

[Utsikt]

This is a good point, although I would argue that depending on what the ADE is it might be the same for both.

Sure. But we can’t know what the ADE might be, so I’d rather risk the severe than the very severe, even though I’d prefer to start with the moderate.

@Jonathan Edwards why severe/very severe?

 

[V.R.T.]

I’d prefer to start with the moderate.

Surely when you do a drug trial its best to start with people who are the most afflicted by a disease?

I understand excluding very severe because of their extreme vulnerability, and why F&M now exclude mild cos of fluctuation, but I think excluding severe would be a mistake personally.

 

[Jonathan Edwards]

@Jonathan Edwards why severe/very severe?

I think it is reasonable to restrict treatment to a small group who feel they have nothing to lose.

 

[V.R.T.]

I think it is reasonable to restrict treatment to a small group who feel they have nothing to lose.

I think with the exponential level of disability increase with MECFS severity, everybody feels they have a lot to lose. As a severe pwME who has experienced very severe I know I do.

 

[Utsikt]

I think it is reasonable to restrict treatment to a small group who feel they have nothing to lose.

I’m not sure that argument sits right with me. It feels a bit exploitative when the patients aren’t already dying.

But I’m not sure it’s better to limit it to people that feel they have something to lose.

So perhaps making sure the patients aren’t suicidal and are otherwise of a clear mind is the best we can realistically do.

I think with the exponential level of disability increase with MECFS severity, everybody feels they have a lot to lose. As a severe pwME who has experienced very severe I know I do.

I do as well.

Surely when you do a drug trial its best to start with people who are the most afflicted by a disease?

I understand excluding very severe because of their extreme vulnerability, and why F&M now exclude mild cos of fluctuation, but I think excluding severe would be a mistake personally.

I’d say that excluding mild because they might give poorer data is valid. And excluding very severe because of vulnerability is valid.

But you can use the same argument about the severe. Or even just taking the purely utilitarian perspective - the cost to society is higher if a severe becomes very severe than if a moderate becomes severe due to the massively increased need for help at the lower end of the scale of functioning.

You’d obviously flip the argument if the treatment works - then the most severely affected should be prioritised. But that’s a different discussion.

 

[Felis Catus]

I think with the exponential level of disability increase with MECFS severity, everybody feels they have a lot to lose. As a severe pwME who has experienced very severe I know I do.

Me, too but I'm not sure how many mild or moderate patients really understand the level of disability with severe or very severe ME/CFS. Just based on "advice" I see mild/moderate giving to severe/very severe.

 

[fresh_air]

If we want to go down that way, what about something like Tacrolimus, which is approved already?

"Tacrolimus is a macrolide calcineurin inhibitor. In T cells, activation of the T cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor nuclear factor of activated T cells (NF-AT), which moves to the nucleus of the T cell and increases the activity of genes coding for IL-2 and related cytokines. Tacrolimus prevents the dephosphorylation of NF-AT." (Wikipedia)

 

[Kitty]

I’m not sure that argument sits right with me. It feels a bit exploitative when the patients aren’t already dying.

I know what you mean. But there are people who know, quite rationally, that they may not be able to carry on living with it indefinitely. For some of them the risk of not finding a treatment might be substantially higher than the risk of adverse drug effects.

Of course there's still an ethical issue—that very vulnerability could be exploited. Perhaps it could be mitigated by limiting a trial to people who're above X age, have been ill at least X number of years, and leaving a gap between initial recruitment and trial start to give them reflection time.

 

[V.R.T.]

But you can use the same argument about the severe. Or even just taking the purely utilitarian perspective - the cost to society is higher if a severe becomes very severe than if a moderate becomes severe due to the massively increased need for help at the lower end of the scale of functioning.

I sort of see your point but when I was moderate I could mostly manage by myself around thr house and now I am severe I need care with so many things every day and struggle to put together a basic snack in the kitchen while sitting on an office chair.

Also I feel like we do need to know if drugs work in severe people, and only studying moderate exclusively feels very limiting.

Also I don't know how very severe people feel about the idea of being excluded from drug trials.

 

[neophyte32]

Hello everyone,
excuse me, but I'm experiencing severe brain fog with quite complicated cranial pressure, and I don't really understand why you're now talking about T cells. Are there clues from a study? Or just a hunch?

Regarding the trials for severe/very severe cases, I'd be willing to take a big risk. I haven't been independent at all for the past 15 months; my wife has to give me washcloths because I can no longer shower, bring myself food in bed... in short, at this point, we have nothing left to lose. At least, that's my point of view.

After all, we risk getting no results and having all the trials canceled...

 

[Jaybee00]

Are there any physician researchers in the ME/CFS field now who could conceivably take a trial like this on?

Sure tell Polybio that you have really good evidence it kills spike proteins. They’ll be on it in days.

{sarcasm alert}

 

[Jonathan Edwards]

If we want to go down that way, what about something like Tacrolimus, which is approved already?

Drugs like tacrolimus tend to do rather little to diseases that we understand a lot better and seem to be T cell dependent. They also tend to be quite toxic. The attraction of something like Campath is that we know exactly what it does and it does it pretty comprehensively and although the effect is irreversible for several years in many cases, the dangers, at least as reported in RA trials, were modest.