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

[Pibee]

seems CD19 wont be enough for MS, ... at least based on OCB just dropping in 1 patient and persisting in other, that's discouraging. It might still work very very well better than whatever they have now (like CD20 monoclonals or HSCT), but I read and think these 2 case reports indicate you need to reset plasma cells as well to fully cure MS.

and it's a bit weird report, unclear if they had RRMS or PPMS...

 

[Jonathan Edwards]

seems CD19 wont be enough for MS, ... at least based on OCB just dropping in 1 patient and persisting in other

Probably right but I would be careful about using oligoclonal bands as an endpoint in the shorter term (less than a year). The kinetics of response is likely to be very complex and in most patients the clinical aim is to prevent new demyelinating foci. Nobody knows what determine those but it may not relate to persistent antibody production the CNS compartment directly.

It will be very interesting to see. I agree that more clinical detail would have been helpful.

 

[EndME]

The enchanting canvas of CAR technology: Unveiling its wonders in non-neoplastic diseases

Summary
Chimeric antigen receptor (CAR) T cells have made a groundbreaking advancement in personalized immunotherapy and achieved widespread success in hematological malignancies. As CAR technology continues to evolve, numerous studies have unveiled its potential far beyond the realm of oncology. This review focuses on the current applications of CAR-based cellular platforms in non-neoplastic indications, such as autoimmune, infectious, fibrotic, and cellular senescence-associated diseases. Furthermore, we delve into the utilization of CARs in non-T cell populations such as natural killer (NK) cells and macrophages, highlighting their therapeutic potential in non-neoplastic conditions and offering the potential for targeted, personalized therapies to improve patient outcomes and enhanced quality of life.

https://www.cell.com/med/fulltext/S2666-6340(24)00128-4

 

[Jonathan Edwards]

A review from authors in Wuhan!!
And published in something called 'Med'
Is this AI??

 

[Jaybee00]

It’s an enchanting canvas!!!

 

[Jonathan Edwards]

Generally speaking you want a canvas to be evenly primed, either with rabbit size or some modern emulsion foundation, and to have some texture but no other features - certain not irregularities.

Maybe the AI picked the wrong metaphor?

 

[Jaybee00]

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1298815/full

Concurrent remission of lymphoma and Sjögren’s disease following anti-CD19 chimeric antigen receptor-T cell therapy for diffuse large B-cell lymphoma: a case report

 

[Sean_Liu]

seems CD19 wont be enough for MS, ... at least based on OCB just dropping in 1 patient and persisting in other, that's discouraging. It might still work very very well better than whatever they have now (like CD20 monoclonals or HSCT), but I read and think these 2 case reports indicate you need to reset plasma cells as well to fully cure MS.

and it's a bit weird report, unclear if they had RRMS or PPMS...

Which report did you see? I saw there were 2 progressive MS patients received CAR T in March and it is too early to assess efficacy.
Another question I have is how to know the duration of CAR T cells. Dr. Schett's adult patients received CAR T only last < 3months which is great for a reset. But the adolescent girl's CAR T cells are still present at 6 months at the time of publication (she is also a patient of Dr. Schett). Obviously you do not want wiping out CD19+ cells for too long after reset but it is said with the current construct CAR T cells can survive up to a few years.

 

[Sean_Liu]

I never expected that I, as a MECFS/Sjogrens/POTS/SFN person can be cured by CD19 alone, I feared for 2 yrs it will require BCMA.

Seems Chinese recognized this earlier so do more of these BCMA alone trials!

As it is already clear significant % of autoimmune illnesses and/or patients is not okay w CD19.
The problem is in USA & EU, there are no trials with BCMA, and especially no with dual.
(only Chinese Gracell in USA should be CD19-BCMA).
I heard prof. Schett saying giving both would be too much, but BCMA alone, can not reset. & Will take a lot of time to do BCMA in the West, especially with the T-cell lymphoma risks.


According to anti-smith aabs and latest tests, I have lupus too, but i even forget about it 99% of the time as this fckr POTS/SFN/Sjogrens is so stubborn stuff.

TLDR:
In other words... A graph is worth a thousand words..

From Schett's 15 case series w CD19

View attachment 21172

Gracell is now part of AstraZeneca. Don't know how it is going to affect their strategy. For you, I think it remains a question how much your SSA is coming from plasma cells vs plasmablasts. And anti-smith is known to be likely from plasmablasts. I would suggest CD19 CAR T first if CD19-BCMA is not readily available. Well the cost is another thing... but it is possible that CD19 CAR T will give you quite some relief and while waiting for the BCMA CAR T, allogenic CAR T will bring down the price significantly.

Did you see the recent BiTEs study from Dr. Schett? Maybe applying for off label use of Teclistamab will give you some benefits while waiting for CAR T?

 

[Sean_Liu]

I know CAR-T aimed at B-cells for antigens of MusK and DSG3-CAART for pemphigus vugaris, failed, with or without chemo preconditioning. Do you think Sjogren's w SSA or SSB would be a good target for CAART? I think I saw study in mice for SSB, but makes no sense with a disease with so many antibodies, or?

Do you think some illnesses wouldn't relapse from BCMA because the antigen is intracellular so B-cells wouldn't get activated? I see some BCMA only studies but I am wondering what to expect, how long the remission lasts ...

there are 2 case reports with RA, 1 Schett's SLE patient and her RA is 'gone' and one is in BCMA reports on NMOSD, it says:

In addition, the patient with rheumatoid arthritis (RA, Patient 10) showed improvement in RA disease activity at 12 weeks post infusion. Disease Activity Score in 28 joints and erythrocyte sedimentation rate decreased from 4.698 (indicating an active status) to 1.987 (indicating a remission stage), and tender joint counts decreased from 24 to 0 in Patient 10.
.



Chinese have anti-CD7 studies but I think I was told it's absolutely reserved for super severe patients as it's way too risky?

May I ask are you sure 1 Schett's SLE patient's RA is treated well with CAR T CD19? I did not see it in his publication. Maybe I did not read it carefully enough?

 

[Sean_Liu]

It will be soon 3 years for the first [German] patient (it was done 1+ years earlier in China and because they used CD19-BCMA they have even better results).

The data from Chinese researchers from January/2023. I spoke to the main researcher last weekend, who is a hematopathologist in NYC, and I am really impressed, he confirmed and showed me data/graphs this is all still valid -nobody relapsed and still, nobody has autoantibodies, so basically they have data for 4+ years now, for their first patient. And unlike with CD19 alone, they managed to get rid of all antibodies. I asked him to treat me multiple times as he previously mentioned that option, but their hospital board in China is very strict and only treated for now lupus nephritis, and a couple of other life-threatening AID cases, like ITP, so no way for me, for only QoL indication... which confirms they're really serious and by the book!



The photo is from 1st German patient 1000th-day celebration in December.
I talked with her and published on this site:https://autoimmunecar.com/patients-experiences
(the site is barely started so I postpone sharing but I guess why wait... )
View attachment 21175

Dr. Thomas the lupus encyclopedia doctor heard one of Dr. Schett's patient's SLE relapsed (not verified)- have you heard anything about it?

 

[Jonathan Edwards]

May I ask are you sure 1 Schett's SLE patient's RA is treated well with CAR T CD19?

I think it may be important to note that 'RA' simply means an inflammatory arthropathy of a pattern probably due to small immune complex activation of macrophages through CD16. In SLE the complexes may involve different antigens from stand alone RA so the response to treatments may not tell us anything about response in RA. It is all very complex.

 

[Jonathan Edwards]

And anti-smith is known to be likely from plasmablasts.

In our original report Anti-Sm did not go down over 6 months with ritux so probably from long lived plasma cells?

 

[Pibee]

In our original report Anti-Sm did not go down over 6 months with ritux so probably from long lived plasma cells?

I tested 3x over the reference range for anti-smith in 2023, now it was negative. I bet they didn't even test ENAs after ANA 1:80, just wrote its negative.. Because i wanted them to test it, they barely agreed... And the positive was in the other hospital but same testing kit I believe... What to make out of this...My ANA is 1:160 without IVIG, but since IVIG is 1:80.

Dr Yupo Ma told me anti-smith is one of those that go away easily, only SSA SSB he said are hard cookies

I have seen Celltrend after CD19, in a POTS pt, all GPCR aabs atill there still very high.. (thought of sharing without going into discussion how valid the test is)

 

[Pibee]

Dr. Thomas the lupus encyclopedia doctor heard one of Dr. Schett's patient's SLE relapsed (not verified)- have you heard anything about it?

a SLE patient with RA is in remission of RA from cd19. I think the same patient has SSA, not sure..and had a flare up of nephritis so you can count that as a relapse, but with staying positive to antibodies was she even in remission?! And I think myositis patient also relapsed , but they didn't even share that patients anti-jo1, RF and scl100 after cd19 so we can assume it never went away.
American/Chinese researcher dr Yupo Ma told me this is all to be expected & he has seen relapses from CD19 alone when antibodies weren't fully gone. his product is dual BCMA-CD19

 

[Pibee]

Gracell is now part of AstraZeneca. Don't know how it is going to affect their strategy. For you, I think it remains a question how much your SSA is coming from plasma cells vs plasmablasts. And anti-smith is known to be likely from plasmablasts. I would suggest CD19 CAR T first if CD19-BCMA is not readily available. Well the cost is another thing... but it is possible that CD19 CAR T will give you quite some relief and while waiting for the BCMA CAR T, allogenic CAR T will bring down the price significantly.

Did you see the recent BiTEs study from Dr. Schett? Maybe applying for off label use of Teclistamab will give you some benefits while waiting for CAR T?

I have heard of mostly relapses/failures of treatments w CD19 when Sjogrens is also present (usually with neuro illnesses) so i'm glad to skip that.
What surprised me is that it seems that often CD19 doesn't even give a temporary relief if your antibodies are not gone....
Or the relapse is too fast despite drastic initial benefits?! Don't understand why!

Of course they won't mention it much until maybe 6 months or 12 months from now they get IND from the FDA for their BCMA/BAFF CAR-T too
One anti-BAFF already got it (Luminary), they mentioned 4 years ago wanting to target Sjogrens too, but now again only SLE.

CFDA approved BCMA in China is $160K (IASO Bio.. and as you probably know they are starting a trial for MG in USA). And the brands that are still in trials like YaKe cost much much less, if you actually get anyone to get it for you, if you don't qualify for a trial. ...

 

[Sean_Liu]

I think it may be important to note that 'RA' simply means an inflammatory arthropathy of a pattern probably due to small immune complex activation of macrophages through CD16. In SLE the complexes may involve different antigens from stand alone RA so the response to treatments may not tell us anything about response in RA. It is all very complex.

Thank you for educating me on that. I agree. Some RA patients, especially seronegative ones, may not be responsive to CAR T if the pathology is not driven by autoantibodies.

 

[Sean_Liu]

In our original report Anti-Sm did not go down over 6 months with ritux so probably from long lived plasma cells?

Rituximab does not target plasmablasts which probably account for the Anti-Smith. Given the disappearance of that by CD19 CAR T, I think it is not from LLPC.

 

[Sean_Liu]

a SLE patient with RA is in remission of RA from cd19. I think the same patient has SSA, not sure..and had a flare up of nephritis so you can count that as a relapse, but with staying positive to antibodies was she even in remission?! And I think myositis patient also relapsed , but they didn't even share that patients anti-jo1, RF and scl100 after cd19 so we can assume it never went away.
American/Chinese researcher dr Yupo Ma told me this is all to be expected & he has seen relapses from CD19 alone when antibodies weren't fully gone. his product is dual BCMA-CD19

Thank you. It is a bad news to hear that maybe SSA is sufficient to trigger nephritis relapse. But at least we know which direction to work on. Hope that patient can go on for BCMA CAR T. So is myositis one. Yeah I agree, dual BCMA/CD19 will cover the full spectrum from pro-B to LLPC. It is also possible to do sequential CAR T to mitigate the depletion related side effects.

 

[Sean_Liu]

I have heard of mostly relapses/failures of treatments w CD19 when Sjogrens is also present (usually with neuro illnesses) so i'm glad to skip that.
What surprised me is that it seems that often CD19 doesn't even give a temporary relief if your antibodies are not gone....
Or the relapse is too fast despite drastic initial benefits?! Don't understand why!

Of course they won't mention it much until maybe 6 months or 12 months from now they get IND from the FDA for their BCMA/BAFF CAR-T too
One anti-BAFF already got it (Luminary), they mentioned 4 years ago wanting to target Sjogrens too, but now again only SLE.

CFDA approved BCMA in China is $160K (IASO Bio.. and as you probably know they are starting a trial for MG in USA). And the brands that are still in trials like YaKe cost much much less, if you actually get anyone to get it for you, if you don't qualify for a trial. ...

The prerequisite for CD19 to give you relief is that the disease causing antibodies, at least part of which, are coming from plasmablasts. If they are only from LLPC, then there may not be any benefits.

BAFF may not be a good target, if not paired with BCMA, I suspect. Well it is a little tricky because BAFF does affect plasmablast survival so it might be ok. But definitely not LLPC.

CD19/BCMA is the best option for Sjogren's. But if the dual CAR T cannot be offered right now, which one should go first? I feel that CD19 should go first because BCMA CAR T cannot prevent new autoreactive mature/memory B cells differentiating into LLPC after BCMA CAR T cells exhaust. The chance of that is low because CD19 also target plasmablasts. However, if one waits too long between the two separate CAR T, it might happen. Well it is understandable that patients need immediate relief with whatever is available first.