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

A study with dual CD19-BCMA CAR-T, for 13 SLE patients is published, with up to 46 months of follow-up. All patients are in remission besides P11 who received half of the dose (see the quote below)

It seems they have used much less chemotherapy,they mention only 300mg/m2, cyclophosphamide, and only the first 2 patients received any flu (there was no additional benefit it seems). So 3 x less chemo? or they've omitted to write 300 mg x 3 days?

Patient treatment
T cells from peripheral blood obtained via apheresis were transfected to engineer cCAR. Treatment schema is depicted in figure 1A. Patients received a dose of 3×10^6 cCAR cells /kg body weight postcessation of all SLE medications following
conditioning with cyclophosphamide (0.3g per m2 ) and fludarabine (0.03g per m2 ) (Cy/influenza) for P1 and P2, and Cy (0.3g per m2 ) alone for P3–P13. SLE/LN patients receiving immunosuppressing medications may suffer severe lymphopenia
due to conditioning and risk subsequent infection. Given that Cy conditioning has demonstrated comparable efficacy to Cy/influenza, Cy alone was trialled to mitigate this possibility.12 The trial commenced as of 17 September 2019 and 13 patients have received cCAR as of 1 October 2023.
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Also, interesting (and scary) part:

Severe bone marrow suppression was experienced by P11 and therefore inadequate T cell counts were harvested through apheresis. As compassion-focused therapy, P11 received a dose of 1.5×10°cells /kg. This initial dose given to P11 proved to be subtherapeutic, even so, P11 still achieved medication and symptom-free LLDAS for 4 months. Unfortunately, clinically insufficient autoantibody control was observed which indicates that the dose of the initial infusion of CAR T cells is critical. Relapse was observed 4 months following the initial cCAR infusion and as such P11 was reinfused with the target dose. Despite this subsequent dosing (3×10°cells/kg), P11 relapsed 6 months following treatment. Similar relapse has been observed with CD19 CAR T cells, where redosing may result in failure rates as high as 80%. The initial relapse was a result of insufficient dosing, however, the subsequent relapse following reinfusion was likely a result of anti-CAR antibodies. This instance demonstrates the critical importance of a sufficient initial dose. Completing the second reinfusion in closer proximity to the initial dose, or an increased reinfusion dose may be other mechanisms for solving this problem. Strong persistence of cCAR was observed as symptom and MFR were maintained following reinfusion for 6 months despite the presence of anti-CAR neutralising antibodies.
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After the initial dose of 1.5×106 cCAR cells /kg, P11 achieved
symptom-free and MFR that persisted for 4months. Relapse was
observed, particularly in control of autoantibodies which appeared
at 6–8 weeks, indicated by an increase in anti-U1-snRNP, dsDNA,
anti-Sm and anti-nucleosome
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Strange that even dsDNA came back, which never happened from what I know with German patients treated with only CD19, even.

Makes sense that the dual needs higher dose, though? Especially if chemo is 3x lower as well
.

Also, it's interesting that they measured IgA levels in saliva, which seem to come back at 8 months (not yet normal for everyone), and they did renal biopsy:


Immunofluorescence analysis of renal biopsy. The pathology in P3 illustrates the deposition of immunoglobulin IgA, IgM, IgG, complement C3, C1q, and fibrin (FIB) in the kidneys before cCAR and 6 months after cCAR treatment.
As can be seen above, following cCAR treatment, except for a small quantity of IgM deposition in the renal tissue, all other glomerular insults were significantly reduced or absent.
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From the recent report with dual BCMA CD19
Screenshot-2024-05-26-09-15-48-097-com-facebook-orca-edit.jpg


Why would anti-SSA persist until 100+ days and then rapidly fall, what would be the explanation for this, if dual deleted every plasma cell, @Jonathan Edwards?
 
Pibee said:
Why would anti-SSA persist until 100+ days and then rapidly fall, what would be the explanation for this, if dual deleted every plasma cell, @Jonathan Edwards?
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That looks like a calibration artefact to me. You have to be ever so careful about cross-calibrating these assays. Part of the problem is that the scale changes from 10 to 60 days per gradation. But there is something else odd going on. Antibody profiles after B depletion are always heterogeneous between patients. The right hand profiles are very similar but one time point shifted. That's odd.

It is conceivable that there is a biological mechanism that accelerates antibody depletion later but I don't think this is a question of deleting plasma cells - that would produce very early fall. I think plasma cells are dying from ageing after deep memory B cell depletion.

I also think one should be cautious about interpreting the zero line. There is no zero in an antibody assay. It is always a construct of calibration and a rather shaky one at that.
 
That is a bit strange since it suggests that total IgG goes down quicker than autoantibody.
I think there may be an awful lot of uncertainty in these kinetic profiles. I don't like the way they have played around with the axes much.

It does look as if profound clearance of antibodies and presumably plasma cells occurs, by whatever means. That to me is the crucial experiment to do - to be prepared to get Ig levels very low. If it works then our original proposal will be validated after all. In other words you can break a B cell lineage cycle without killing T cells and get long term remission.
 
Well IASO Bio also has such graphs with even more clear IgG to near 0, with only BCMA.
But in their recent paper they mentioned something like "the persistence of CAR-T cells in autoimmune patients should be improved to keep an ongoing remission"
That got me thinking if someone relapsed from those 13 patients
 
Pibee said:
something like "the persistence of CAR-T cells in autoimmune patients should be improved to keep an ongoing remission"
That got me thinking if someone relapsed from those 13 patients
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They may assume that something else will bring back autoreactive B cells. Most immunologists do.
The problem with one or two relapses is that the clinical experiment is unlikely ever to be quite as clean as testing the theory needs. But if relapse is inevitable even with complete clearance of B lineage then we would have been wrong.
 
Dual cd19-bcma SLE researcher, from icellgene, told me to ask 6 months data when doing it...to be sure it's a reset...I guess whoever relapsed for now was within 6 months.
He was seeing significant number of relapses w only CD19. He is very against it.
But I wonder, for more less isolated LN, would still be logical to keep that as a first choice, despite ANA and some antibodies staying positive in some people.
 
Pibee said:
Dual cd19-bcma SLE researcher, from icellgene, told me to ask 6 months data when doing it...to be sure it's a reset...I guess whoever relapsed for now was within 6 months.
He was seeing significant number of relapses w only CD19. He is very against it.
But I wonder, for more less isolated LN, would still be logical to keep that as a first choice, despite ANA and some antibodies staying positive in some people.
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I can't really follow what you are saying there.
6 months is much too short to judge reset. It is more like 5-8 years. Relapse with heavy duty immunoablation tends to come in over five years. With rituximab it continues for up to 8 years.

To be reasonably convinced of some resets I would like to see less than 40% relapse out at 5 years. A few relapses earlier may just mean that the regimen hasn't taken well for some cases.
 
I guess, he might mean that because I cant really wait and be untreated for 5 years, I should at least see 6 months data, to see I am not getting a really weak product that wont keep several years of remission (he was saying in a sense to buy myself few years and then repeat it if needed when better/more products available), because patients relapsed in less than 6m after some bad on€s, and I spoke to some of those patients who had a relapse in that time- like, I think 4 months, (in his published study there is a case of a very fast dsDNA return after getting to 'zero', they blame too low initial dose of CART).

I guess because B cell come back faster after CART than after monoclonal antibodies, the relapse when no reset occurred would be faster too!?
 
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447301787_10237236290186484_5890836023704561743_n.jpg

BCMA-CD19 bispecific CAR-T therapy in refractory chronic inflammatory demyelinating polyneuropathy

hope this means for SFN too

CAR T-Cell Therapy Seems Safe and Effective in CIDP
A new case report of bi-specific CAR T-cell therapy targeting BCMA and CD19 for treating chronic inflammatory demyelinating polyneuropathy (CIDP).
  • 44-year-old male with recurrent numbness and weakness in the hands and feet.
  • Side effects included fever and a transient increase in interleukin-6 levels managed with acetaminophen, mild cytokine release syndrome resolved within 2 weeks, and hypotension resolved after 2 weeks of bed rest and hydration.
  • The patient's condition markedly improved, with almost complete muscle strength recovery by day 180 and restored walking ability.
  • Post-treatment, he had no anti-GM4 or anti-GD3 antibodies and could discontinue all immunosuppressive agents without relapse.
  • Initial treatments with intravenous immunoglobulin and high-dose pulse intravenous methylprednisolone improved symptoms but did not achieve complete remission.
  • The researchers reported no other CAR-T cell therapy-related toxicities and noted this as the first reported case of CIDP treated with bispecific CAR-T therapy showing apparent efficacy.
full report>




https://www.sciencedirect.com/science/article/pii/S2949928324000440?fbclid=IwZXh0bgNhZW0CMTAAAR3dSGyK3EvShnK9r6v5RFYrzbsu3IZFyXvMRiYs_a-2K9eRQBi-ABOydeA_aem_AaNYgWO2UGpG_qFgp5NLEEnX-dMRsv2piP7BeK1U3ZUPXDPLClk-aNQ2jvfhoCtSo7GD_5khJ4ZT1KU3HNygobNJ#xd_co_f=MjQzMDFkZWEtYTllZi00YTcwLWE5YWItODVkMjlhYTFmMDg2~
 
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Pretty sure I found a study years ago where 60-70% of CIDP had SFN too, and that the same drugs are used (found effective?) like IVIG, cyclophosphamide, Vyvgart (?) and both SFN and/or CIDP co-occur with Sjogrens... , I'll keep my hope.
 
This one is also interesting :

A woman successfully became pregnant and gave birth to a daughter after CAR-T treatment for SLE
"Thanks to the advanced technology of the Municipal People's Hospital, becoming a mother successfully is the happiest thing for our whole family." On May 27, Xiao Du from Huangpu Town took her daughter to the Rheumatology and Immunology Department of the Municipal People's Hospital for a follow-up examination. When the doctor told her that all indicators were good and the child was relatively healthy, she was excited and burst into tears. It is understood that this is the first case of a systemic lupus erythematosus (SLE) patient in our city who recovered after chimeric antigen receptor T cells (CAR-T cells) treatment and successfully became pregnant and gave birth to a healthy baby. It is also the first successful case of childbirth after CAR-T treatment in the world.
https://www.zsnews.cn/health/index/...cARiKfkreSEg44WGMCg9-abxZYclEMaC02QnorOBjx_HW
 
and this especially:
First case report from China with donor (allogeneic) off the shelf CAR-T cells
lower chemo dose used
her disease activity score - SLEDAI went from 18 to 0
After a series of rigorous examinations and evaluations, Li Ting was selected to participate in the clinical trial. The experimental drug that Li Ting participated in fully transformed allogeneic immune cells through gene editing technology, effectively avoiding the risks of GVHD (graft-versus-host disease) and HVG (transplant rejection) that may exist in allogeneic cell transplantation. Compared with autologous CAR-T, this clinical study uses healthy donor blood samples for production, does not require the collection of autologous cells in advance, and can be used immediately. It has a definite clinical efficacy and high safety. At the same time, because the dose of lymphocyte-clearing chemotherapy (lymphocyte clearance) is lower than that of autologous CAR-T, the possible clinical risks are further reduced.When universal CAR-T cells were infused into Li Ting's body, something magical happened. Her physical condition began to improve significantly, and there were no serious adverse reactions such as infection. Her hair loss, erythema, edema, urine protein, hematuria, and joint pain improved significantly, and the systemic lupus erythematosus score dropped from 18 points before treatment to 0 points, and she gradually stopped all hormones and immunosuppressants.
https://mp.weixin.qq.com/s/HNSUD4-3pF3vvWtvi5K9Z
 
Pibee said:
something magical happened. Her physical condition began to improve significantly, and there were no serious adverse reactions such as infection. Her hair loss, erythema, edema, urine protein, hematuria, and joint pain improved significantly, and the systemic lupus erythematosus score dropped from 18 points before treatment to 0 points, and she gradually stopped all hormones and immunosuppressants.
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Reminds me of the cases we treated with rituximab 25 years ago!!
 
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