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

‘It’s all gone’: CAR-T therapy forces autoimmune diseases into remission
https://www.nature.com/articles/d41586-023-03968-6

Engineered immune cells have given 15 people with once-debilitating autoimmune disorders a new lease on life, free from fresh symptoms or treatments. The results raise hopes that the approach — called CAR-T-cell therapy — might one day be extended to a variety of other conditions fuelled by rogue immune cells that produce antibodies against the body’s own tissues.

All 15 participants, who each had one of three autoimmune conditions, have remained disease-free or nearly so since their treatment, according to data presented on 9 December at the American Society of Hematology meeting in San Diego, California. The first participants were treated more than two years ago.
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Other groups have since taken up the approach and reported similar results. Earlier this month, another team added a fourth autoimmune disorder called myasthenia gravis to the list of successes2. Researchers are beginning to wonder how long the final list will be. “We’re just at the beginning,” says Marcela Maus, who designs CAR-T therapies against cancer at Massachusetts General Hospital in Boston. “There is so much that can be done that was unthinkable just a decade ago.”
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CAR-T therapies harness the immune players called T cells. T cells are removed from the person being treated, genetically engineered to produce proteins called chimeric antigen receptors (CARs) and then reintroduced to the person’s body. In many therapies, the T cells are tailored to recognize a protein made by immune cells called B cells. When reintroduced, the CAR T cells will target the B cells for destruction — a useful feature for treating cancers caused by abnormal B cells.
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For now, Müller lapses into a dreamy smile as he marvels over the remarkable recoveries he has seen: the man who struggled to walk 10 metres before his treatment and now routinely walks 10 kilometres around town, for example. “These are young people that have been spending more time with their doctors than with their friends,” he says. “They would describe their breakfast as a handful of pills that they are just shoving in.”

 

Maybe at last we have what I was hoping for twenty five years ago - a powerful enough B cell depletion therapy to produce long term cure. If so, I shall die happy.

 

It seems amazing.. Do you think this could mean anything for ME?

 

I know a patient who has significantly disabled with Long COVID, and for a while was focused on MAID. Awful situation. She is lucky and has wealthy family, she got CAR-T in a private clinic and is now in remission.
I think its clear there is a sub-set of patients with ME and LC that have some form of b cell mediated illness, and that we simply cant have dangerous meds like cyclo and ritux (ritux not even really working), potentially daratumumab is on the horizon as well but im sure if we even see efficacy in ME and LC patients it wont be close to the levels of what CAR-T can do.
As a brit who is currently having to pay out of pocket for immune-based medication so I can function, i really hope the NHS listens to these results, and starts trials for known autoimmune diseases and eventually ME/LC.

 

No, I am afraid not.

CAR-T therapy does the same as rituximab. The only difference is that you may not need to repeat it. If CAR-T was going to work in ME I think there should have been temporary responses to rituximab and the phase III trial indicated that there weren't.

The rituxmab trials also highlighted the dangers of over interpreting individual histories. Several patients given rituximab on the open label extension seemed to show perfectly timed responses, yet I think we have to conclude that these represent temporary mind over matter (placebo) effects. One or two patients remained well long term - which does not really fit with an effect of rituximab anyway - and presumably were just lucky enough to have got better for other reasons at that point.

 

Not gonna lie, this brought a tear to my eye.

 

To be clear CAR-T is not "just like rituximab", although it could be fair to say its approach would be similar.
Rituximab is a crap drug in autoimmunity, weak and there have been many failed trials for diseases such as sjorgens, https://pubmed.ncbi.nlm.nih.gov/27431352/ ,lupus: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548300/

The difference here is that ME/CFS patients are treated like such crap that it only took one failed trial to convince patients and doctors (not all thanks Fluge and Schebenbogen!) that is was not b cell mediated. LC is changing this though, and increasing funding in the right areas. Once something properly sticks in terms of outcomes for patients, we are onto a winner.

CAR-T is a COMPLETE revolution in terms of the depth and impact, alongside binding to a different site (ritux=CD20 VS CAR-CD19).
It differs in so far that you can say its like the difference between decaf and fully fledged caffeine up to the eye balls intervention. This truly truly is a revolution, its not hyperbole.

Thank GOD we are seeing a new generation of doctors and researchers come in and revolutionise this field

 

I want to say that I do know that you are a specialist in that area, I have talked to other specialists, though. (I am not even close to being a specialist myself.) They told me that Rituximab is not the same as CAR-T in terms of b-cells, as there might be a difference of penetration in terms of tissue resident b-cells for respective modalities.

 

CAR-T and monoclonal antibodies can not be compared. Rituximab targets CD20, but for example, monoclonals that target CD19 badly failed in lupus, while CAR-T that targets CD19 cures the majority of lupus patients (not all because some need to target BCMA too for LLPC -long-living plasma cells).
Lupus is easier to manage than Sjogren's, which is the most common cause of autoimmune small fiber neuropathy and POTS, so Sjogren's needs also BCMA+CD19 most likely because despite CD19 CAR-T anti-SSA antibodies remained.

This is information after speaking to all researchers in the field in Germany, China and USA, I have been focusing on CAR-T for over 2 years.

For SFN part of Sjogrens (which is where many undiagnosed MECFS patients fall) it is unclear for how many patients CD19 will be enough, as it is more responsive than the gland involvement, but less than SLE. For now 1 case report on POTS/sFN

The graph shows how superficial the Mab depletion of B cells is, and the thing is if your autoantibodies are produced by LLPC, it is possible to have zero response to RTX which doesnt hit LLPC. Or to worsen as some patients if BAFF (B cell activating factor) goes up after RTX which makes autoantibodies rise even higher than before RTX

I spoke to thus far 22 CAR-T autoimmune patients (one had POTS and SFN before CD19 CAR-T), so they are SLE, Sjogrens, MG, LEMS, AAG, myositis, ITP, RA and scleroderma group, all of them failed rituximab, belimumab, IVIG, efgartigimod, daratumumab, cyclophosphamide...even bortezomib.
You cant stop at RTX and say if it didn't help it's not autoimmune.
But I just think SFN diagnosis is more important because it's clearer pathology than MECFS.

the full talk where this graph was presented is here:

 

“At this stage, however, it’s unclear how much of this success is due to the CAR-T therapy as opposed to the chemotherapy that killed many of the participants’ pre-existing immune cells, cautions Ruella. That might have helped to wipe out the errant B cells.”

In other words it might be the cyclophosphamide (or fludarabine https://en.m.wikipedia.org/wiki/Fludarabine) that is given in this treatment that is curing them.

 

Nope, all of those patients failed cyclophosphamide, and with CAR-T they dont get much higher cyclo dose than the standard monthly dose for lupus nephritis! I spoke to almost all German patients and researchers.
Whoever commented that just wanted to say something skeptical.

Cyclophosphamide doesnt get your dsDNA from 4000 to 5 which happened for patient 1, who was basically dying. Cyclo is very mediocre at knocking down antibodies, I think daratumumab does more.

 

The patients who received CAR-T already failed Cyclophosphamide and the Fludarabine given is not a therapeutic dose. It's only to clear cells for CAR-T expansion.

Also, anyone who says Rituximab and anti-CD19 CAR-T do the same thing, frankly have no idea what they're talking about.

Btw, I am a scientist studying autoimmune diseases who has a partner with extremely severe ME/CFS, POTS, SFN, etc... this is all I spend my energy on.

 

Well, I have my ways I am not a clinician, I am just obsessed with CAR-T for almost 3 years

and not sure what data is confidential, exactly, surely not the one i got from the patients themselves As they are allowed to talk about their own life

Same applies to the researchers, as you might know most of them are enthusiastic about their work and happy to discuss it sometimes.

Also, I shared this, despite it's not something new and i've been in contact with some CAR-T autoimmune pts for over a year, to reassure patients to not get sidetracked by skeptic comments like if the chemo itself cured these patients - as every clinician and most researchers know the chemo cant do this, that is the problem with chemo to begin with!!

I am preparing for CAR-T myself for a long time, and was applying to studies in China but I admit being very afraid so I met all the researchers and patients I could find while trying to be more sure in my decision to do it. When I started asking about this there was no data and nobody could tell if CD19 is enough for neurosjogrens, now it seems it's basically not enough /but it's individual in the end too.
Same for chemo preconditioning, the debates if it's even needed or the dose can be reduced, I am inclined to believe for now they wont be able to remove chemo part fully, but they did give 1 patient only half of the chemo dose and it still worked!

 

Norwegian rituximab trial failing doesn’t rule out an autoimmune process. In this meta-analysis of 4 trials of rituximab for Sjogren’s, rituximab didn’t do anything for the core symptoms including fatigue:

https://www.sciencedirect.com/science/article/abs/pii/S1297319X17301318

 

Yes, plasmablasts go to the bone marrow to commit to plasma cell lineage, but they are also still found in some tissues. CD138 is highly expressed for LLPCs, but CD38 and BCMA have been chosen targets due to their still relatively high expression in LLPCs, but also coverage of plasmablasts / some memory B cells. CD38 is targetted by Daratumumab, which has shown pretty remarkable results in a small number of patients with lupus and Sjogren's. Two of the six approved CAR-T therapies in the USA for cancer target BCMA for multiple myeloma, so it might be best to repurpose these if plasma cells are to be targetted in autoimmune diseases.

 

The point I was making is that both rituximab and CAR-T therapy target B cells rather than plasma cells - either via CD20 or CD19. CD19 antibodies have been around a long time but CD20 was identified early as a good target for antibodies. The situation is different for T cells so CD19 may well be the better option.

But both are still removing B cells. Rituximab removes the vast majority of B cells and autoantibody levels fall dramatically in some diseases - repsumably because they are based on production from short lived plasma cells that need then to be replaced. Diseases due to antibodies from long lived plasma cells are not going to be helped much in the short term by either antibody or CAR-T therapy.

I quite agree that CAR-T therapy has much greater potential in terms of depleting B cells more deeply and for a longer time and so it might well produce long term cure where rituximab did not. But that is a different point.

The key point for me is that if ME were due to autoantibodies from short lived plasma cells the rituximab and CAR-T therapy should both show significant benefit - and rituximab didn't. If the autoantibodies are From long-lived cells CAR-T therapy might produce a noticeable effect after five years or so but that on its own is pretty unhelpful and no trial is likely to pick it up.

The original rationale for using rituximab was in fact not so much removing autoantibodies that drove inflammation directly as removing clones of B cells that perpetuated the production of further clones targeting the same antigen. That is where I see CAR-T therapy as having a distinct possibility of being different - but the pharmacodynamics are extremely complex, as Jo Cambridge and I discovered working on antibody profiles over a period of ten years.

 

@siobhanfirestone
Do you know more details about patient history / anamnesis and clinical picture & Symptoms?
Typical ME CFS (strict guidelines e.g. with PEM)?
How long sick ?
Measurements e.g. antibodies, etc?
Why was decided on Car-T ?
Which clinic was giving access to Car-T based on what (e.g. which markers?

Understanding each Anecdotal Remission of (specially) severe patients in detail is important.
(as we lack the proper research any other immune dysfunction illness has)