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

[Jonathan Edwards]

I don't really understand why you're now talking about T cells. Are there clues from a study? Or just a hunch?

We have been homing in on T cells as plausible mediators for ten or more years now. B cells were also on the menu but there are lots of things about ME/CFS that fit better with a T cell response (like the triggering by viruses and mostly small or atypical bacteria and relatively early age peak incidence). I don't see anything like as clear a model as we had for using B cell depletion in common autoimmune diseases but if you take Fluge and Mella's approach of testing a plausible idea in an untreatable condition I think T cell targeting is justified.

If nothing else, if we found that comprehensive t cell blockade/depletion had no effect on established ME/CFS that would be important evidence for established disease being perpetuated largely by nervous system signalling. There remain other options within the immune system but the absence of a major response to corticosteroid or any response to rituximab do make those look less likely to me.

 

[Jonathan Edwards]

I agree that one has to be very careful about not recruiting people who are vulnerable but I think Kitty's comment fits with the way I view it. There are people who remain very lucid and balanced in their arguments who clearly feel that carrying on as they are has no merit. I personally doubt that T cell depletion would make anyone worse. I think we would have had some sort of signal of that from the fairly extensive use of Campath in the past. The counter to that of course is that we have not heard of any miraculous recoveries. But knowing one way or another whether T cell depletion made a difference seems to me something that could be of great importance to future research directions.

There is of course the argument that T cell targeting should be used early, on the basis that T cells may be most important early, but I am not convinced it would be ethical to do that first. Early disease remits or stabilises in a significant number of people.

 

[neophyte32]

We have been homing in on T cells as plausible mediators for ten or more years now. B cells were also on the menu but there are lots of things about ME/CFS that fit better with a T cell response (like the triggering by viruses and mostly small or atypical bacteria and relatively early age peak incidence). I don't see anything like as clear a model as we had for using B cell depletion in common autoimmune diseases but if you take Fluge and Mella's approach of testing a plausible idea in an untreatable condition I think T cell targeting is justified.

If nothing else, if we found that comprehensive t cell blockade/depletion had no effect on established ME/CFS that would be important evidence for established disease being perpetuated largely by nervous system signalling. There remain other options within the immune system but the absence of a major response to corticosteroid or any response to rituximab do make those look less likely to me.

As always, thank you. It's very clear. But isn't one of your hypotheses precisely a signaling problem in the central nervous system/hypothalamus following an infection or other drug-induced shock...? If this T-cell therapy were to fail, would it narrow down the possibilities and advance our cause?

 

[Jonathan Edwards]

As always, thank you. It's very clear. But isn't one of your hypotheses precisely a signaling problem in the central nervous system/hypothalamus following an infection or other drug-induced shock...? If this T-cell therapy were to fail, would it narrow down the possibilities and advance our cause?

I think an important possibility is a signalling problem that depends both on T cells and nerve cells. An important rider to that is at what stage T cells remain important - just for months or throughout. (And I think Chris Ponting's view is quite similar, judging by his recent comments.) So if T cell therapy failed in established cases that would point to established disease being continued purely within neural signalling. If that is the case it is important to know. The data on CA10 and preliminary evidence on CRH cells point to possible ways to address nervous system signalling.

 

[Yann04]

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.

It can always get worse — but I guess some of us in very severe are more like “it could theoretically get worse but that would be antithetical to life, so I have nothing to lose in the sense of that if I lose significant functioning from here I won’t stay alive”.

 

[Utsikt]

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.

Yes, I think that would be a good solution.

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

I’m not advocating for only studying moderates. Just to only pilot in moderates unless you have a strong case for severe being substantially different in a way that would affect the results of the trail.

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

Just from the pilots and early testing. I think Fluge and Mella have already included some severe in the extension of the pilot for Dara, so if the drug has a positive pilot you’d only be talking a couple of years delay for the severe.

Most patients would have to wait longer regardless of severity. And the most severe might actually get access earlier than the rest through compassionate use or similar programmes.

 

[AliceLily]

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.

Yes. The symptom load is full-on too. I am now at a moderate level and if I had not experienced very severe (2 years) and severe (over 10 years) I would have no clue as to how frightening awful this illness can really get.

For myself I would not have wanted to experiment with a drug trial. I was just far too sick and trying to make it through each day. My body was going through so much already and I would not have been able to tolerate more hits. That is just me though and the situation I was in at those levels.

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

I think this is right and our only avenue for a trial. Patients to put themselves up at their own risk.

 

[EndME]

I personally would focus on whatever gives the best data and let sufficiently informed people make their own decisions. Maybe that makes it more likely to exclude a group of moderate people that have more fluctuations or a group of severe people that have had less medical examinations, maybe a minium illness duration, maybe people with a minimum of xyz crashes in a given timeframe or people above a certain age, or maybe not a group of very severe people if that increases the rate of early drop-outs, as well as other things that may depend on context (distance from trial location, sex, cognitive symptoms, othostatic symptoms or sleep symptoms etc).

ME/CFS by definition comes with a high loss of ability and high level of disability. F&M trials suggest that they can be carried out without any deterioration and I suspect it's possible that something similar will be shown in the current trials. As long as people are sufficiently informed I don't see problems beyond that, everybody has lost a whole lot already.

 

[Yann04]

.

For myself I would not have wanted to experiment with a drug trial. I was just far too sick and trying to make it through each day. My body was going through so much already and I would not have been able to tolerate more hits. That is just me though and the situation I was in at those levels.

That’s how I feel aswell at very severe. But I imagine there are potential recruits especially in those who’ve concluded their life is “not worth living” so they don’t mind taking a gamble so to speak.

 

[Utsikt]

F&M trials suggest that they can be carried out without any deterioration and I suspect it's possible that something similar will be shown in the current trials. As long as people are sufficiently informed I don't see problems beyond that, everybody has lost a whole lot already.

We only have data on moderate patients. It’s not surprising they are able to participate safely after selection for patients that think they would be able to participate safely.

Doing it with the severe is a completely different beast, especially if it can’t be done at home. The side effects of the drugs are probably fine, I’m concerned about the side effects of the activities that are required just to participate.

 

[Jonathan Edwards]

Doing it with the severe is a completely different beast, especially if it can’t be done at home. The side effects of the drugs are probably fine, I’m concerned about the side effects of the activities that are required just to participate.

I don't see any problem with this. When I did the first trial of rituximab I made up the drug myself, and monitored the infusions myself, taking the patients' blood pressure and pulse. i could have done that in their home without any problem. I would have liked to have full backup for anaphylactic reactions but in reality these are almost non-existent if you monitor infusions carefully. A single infusion over a couple of hours would be much easier than taking a drug that might produce severe nausea and liver function abnormality over a period of months.

My gut feeling is that treating moderate patients in a pilot study would produce a lemon - no further on. Too many uncertainties. If moderate means able to leave the house and do a certain amount of normal activities outside I don't think that is the right population to test. It is a difficult call but having been through all these considerations before several times I am fairly sure an initial pilot study should recruit severe/very severe cases.

 

[FicaR94]

The gap between B cell trials and T cell research is definitely noticeable. I saw a paper recently on gdT cell mechanisms and it’s frustrating how long it takes to move from lab theory to an actual clinical trial. We really need more focus on those monoclonal antibodies.

 

[Sasha]

I personally doubt that T cell depletion would make anyone worse. I think we would have had some sort of signal of that from the fairly extensive use of Campath in the past. The counter to that of course is that we have not heard of any miraculous recoveries.

Sorry, I haven't been following properly, but has Campath been tried in PwME or when you say its use has been extensive, do you mean for other conditions?

But knowing one way or another whether T cell depletion made a difference seems to me something that could be of great importance to future research directions.

Do Fluge & Mella's observations in the dara pilot give any indications about the likelihood of Campath helping? IIRC, apparent responders and non-responders were split by T-cell levels (?).

 

[Kitty]

My gut feeling is that treating moderate patients in a pilot study would produce a lemon - no further on. Too many uncertainties. If moderate means able to leave the house and do a certain amount of normal activities outside I don't think that is the right population to test.

Yes, there's probably more scope for misdiagnosis in moderate patients.

Severe ME/CFS might offer a clearer separation from possible confounders. For instance, difficulty tolerating the upper body being propped partially upright for any length of time seems pretty distinctive, but it isn't always present in less severe cases.

If they're carefully screened, might ten participants be enough?

 

[EndME]

We only have data on moderate patients. It’s not surprising they are able to participate safely after selection for patients that think they would be able to participate safely.

Doing it with the severe is a completely different beast, especially if it can’t be done at home. The side effects of the drugs are probably fine, I’m concerned about the side effects of the activities that are required just to participate.

I'm not sure it is a different beast. Rituximab trials included severe patients so did Cyclo, even if they were fewer (https://pmc.ncbi.nlm.nih.gov/articles/PMC11265720/), so we do have some data. The current trial is also for severe patients and the open label also included 2. Worries about lack of differential diagnosis can probably be handled on a case by case basis.

Edit: Actually there might be one: the old McKenzie 1998 study of hydrocortisone bills itself as "Low-Dose Hydrocortisone" but gave patients 25-35 mg (equivalent to approximately 6 mg of prednisone) per day -- which from googling seems to be around the RA dose?

I think the Charite study for Long-Covid will have included ME/CFS patients and possible stratified for that. Not sure if they published results though, which would probably anyways indicate they were negative.

 

[Clio]

I'm not sure it is a different beast. Rituximab trials included severe patients so did Cyclo, even if they were fewer (https://pmc.ncbi.nlm.nih.gov/articles/PMC11265720/), so we do have some data. The current trial is also for severe patients and the open label also included 2. Worries about lack of differential diagnosis can probably be handled on a case by case basis.


I think the Charite study for Long-Covid will have included ME/CFS patients and possible stratified for that. Not sure if they published results though, which would probably anyways indicate they were negative.

Has there been anyone with average daily step count of <200 in any of those trials? That's what I would like to see, someone going from 100 to 10 000+ steps per day. Everything to me seems like going from 2000 to 3000 or similar, which is definitely a meaningful improvement for said person but not the shining proof of recovery I want to see from a trial.

 

[MeSci]

Hi, @V.R.T.

You've spelt 'clinical' as 'clincial' in the thread title.

 

[V.R.T.]

Hi, @V.R.T.

You've spelt 'clinical' as 'clincial' in the thread title.

Thanks for pointing that out. I'm a typo factory these days!

 

[V.R.T.]

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?

@Jonathan Edwards if you have a moment to answer this question I'd be very interested to know your thoughts.

 

[Jonathan Edwards]

@Jonathan Edwards if you have a moment to answer this question I'd be very interested to know your thoughts.

I am not entirely sure that Campath could be guaranteed to block any T cell mediated process. It produces uite profound depletion and the target molecule CD52 is, as I understand it, pretty widely expressed on lymphocytes. One slight downside is that it also depletes B cells and that might confound things but with a negative result from rituximab probably not.

Edit: (gammadelta T cells do express CD52)