Yep I am taking a provocative stance, just to illustrate a point…because we have been hearing over and over again that T regulatory cells control MS, but one can say where is the evidence?
Who cares about EAE as we know that is T cell mediated and there blockade of interelukin 2 via genetic means leads to inflammatory effects? However it has been suggested that T regulatory T cells promote remyelination.
Interleukin 2 is known as T cell growth factor and here they give interleukin-two resumably to stimulate the interleukin two receptor on T regulatory cells.. However interukin 2 acts on activated T cells and is a mempry B cell growth factor. Blockade of the interleukin two receptor inhibited MS and reduced T regs, so is it surprising that this study failed to show an effect. They say the “Number of new active brain lesions and of relapses tended to be reduced in IL2LD treated patients, but the difference did not reach significance in this trial not powered to detect clinical efficacy” No sigificant says “Does not work”.….
Now it may not have been powered. So why do the study? But at month-6, the cumulative number of new gadolinium-enhanced T1 lesions was 0.57 (0.85) in the IL2LD group and 1.50 (2.13) in the placebo group (p = 0.08). Wow so close to p=to 0.05) I here people say. This is a trend …but I have to say trend-shmend. Its statistically meaningless.
…..The is a 62% reduction….B ell depletion is in the 95% range and interferons in the 70’s. Whilst the time lines may be different the effects are not that amazing. T2 lesions decreased by a few pecent…Wow
Barkhof F, Kappos L, Wolinsky JS, Li DKB, Bar-Or A, Hartung HP, Belachew S, Han J, Julian L, Sauter A, Napieralski J, Koendgen H, Hauser SL. Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis. Neurology. 2019;93(19):e1778-e1786 = over 90% inhibition in 8 weeks
However, remember its not powered for efficacy…But the risk of doing underpowered small studies that don’t work… means it is harder to convince people to fund a larger study. This study was supported by the French MS Society and it should have completed by 2020 (NCT02424396), The approach was reported to be assessed in “more than 20 different autoimmune diseases” and one suspects there it is not going to be an easy ride……will it happen?
A randomized double-blind placebo-controlled trial of low-dose interleukin-2 in relapsing-remitting multiple sclerosis.Louapre C, Rosenzwajg M, Golse M, Roux A, Pitoiset F, Adda L, Tchitchek N, Papeix C, Maillart E, Ungureanu A, Charbonnier-Beaupel F, Galanaud D, Corvol JC, Vicaut E, Lubetzki C, Klatzmann D.J Neurol. 2023 May 28. doi: 10.1007/s00415-023-11690-6.
Background: Multiple sclerosis (MS) is associated with regulatory T cells (Tregs) insufficiency while low-dose interleukin-2 (IL2LD) activates Tregs and reduces disease activity in autoimmune diseases.
Methods: We aimed at addressing whether IL2LD improved Tregs from MS patients. MS-IL2 was a single-center double-blind phase-2 study. Thirty patients (mean [SD] age 36.8 years [8.3], 16 female) with relapsing-remitting MS with new MRI lesions within 6 months before inclusion were randomly assigned in a 1:1 ratio to placebo or IL-2 at 1 million IU, daily for 5 days and then fortnightly for 6 months. The primary endpoint was change in Tregs at day-5.
Results: Unlike previous trials of IL2LD in more than 20 different autoimmune diseases, Tregs were not expanded at day-5 in IL2LD group, but only at day-15 (median [IQR] fold change from baseline: 1.26 [1.21-1.33] in IL2LD group; 1.01 [0.95-1.05] in placebo group, p < 0.001). At day-5, however, Tregs had acquired an activated phenotype (fold change of CD25 expression in Tregs: 2.17 [1.70-3.55] in IL2LD versus 0.97 [0.86-1.28] in placebo group, p < 0.0001). Regulator/effector T cells ratio remained elevated throughout treatment period in the IL2LD group (p < 0.001). Number of new active brain lesions and of relapses tended to be reduced in IL2LD treated patients, but the difference did not reach significance in this trial not powered to detect clinical efficacy.
Conclusion: The effect of IL2LD on Tregs in MS patients was modest and delayed, compared to other auto-immune diseases. This, together with findings that Tregs improve remyelination in MS models and recent reports of IL2LD efficacy in amyotrophic lateral sclerosis, warrants larger studies of IL2LD in MS, notably with increased dosages and/or modified modalities of administration.
CoI None
Remember this is just an opnion… my opinion.
I think they are ..lolll
Response to theraphy
At the 2023 Consortium of Multiple Sclerosis Centers (CMSC) annual meeting, Tanuja Chitnis, MD, presented data on one of these patients, a 61-year-old male who had non-active secondary progressive MS for over 20 years.2
The individual entered the study with noticeable disease progression despite treatment with ocrelizumab (Ocrevus; Genentech), an FDA-approved anti-CD20 agent. Treatment with foralumab was initiated in May 2021 and was continued for 6 months with a 7-week washout period after 3 months. In addition to showing a safe treatment profile, treatment with foralumab resulted in clinical symptom progression subsiding. Microglial activation, as measured by F-18 PBR06 PET scan, was significantly reduced 3 months after the start of treatment, with reductions sustained after the 7-week washout and at 6 months. Notably, pro-inflammatory cytokines IL-1ß and IL-6 were reduced, as well as Th1 cytokines IFN-y and IL-18.
https://www.neurologylive.com/view/tiziana-announces-planned-phase-2-study-foralumab-progressive-multiple-sclerosis
Well i am not the only one either
Enter sandman …joking…
P.G
The argument about whether or not MS is primarily a T-cell or B-cell disease is academic. Almost all the data suggests that both cell types are involved. Clinical trial data indicate that MS outcomes regarding end-organ damage (brain volume loss) and sustained disability improvement that highly-effective therapies targeting T and B cells, i.e. alemtuzumab and AHSCT, are superior.
If Peresolimab worked in MS, it would prove that MS is likely an autoimmune disease and that T-cells play a role. I don’t need to be convinced about the latter; I think the current evidence is overwhelming.
https://gavingiovannoni.substack.com/p/closing-in-on-the-cause-of-ms-by
Thanks
Ha Ha don’t you know its CD3 trogocytosis onto B cells………. However before I admit defeat on this…one swallow does not make a summer and in some cases it does not make a good drug.
Foralumab is a fully human monoclonal antibody that binds to CD3 epsilon. Subcutaneous in diabetes….deprioritised…..oral in chrohns disease and deprioiritised …which sort of suggests not working great (info from manufacturers website) and now we have nasal non-active SPMS (why would it work given the history with alemtuzumab, HSCT, etc, etc) then Alzheimers and …ALS (when known T cell mediated conditions) and COVID-19. Up the nose helps get stuff in the brain. Phase II in MS expected to start in Q3 2023….I’ll come back in 2-3 years and eat humble pie…but non-active SPMS and immune modulators has been a graveyeard for MS drugs. Hope I’m wrong.
This is an n= 1 from the phase I….7 weeks of treatment and clinical effect and inflammation down…Great,,,but we have been here before so I wont admit defeat just yet.
The manufacturers website says “Currently, Six secondary progressive MS patients are being treated ….. Foralumab has demonstrated ability to activate regulatory T cells that systemically circulate to elicit targeted immunomodulation providing therapeutic benefit to patients…
But good to know abstracts are out,,,,,I’ll have a look
“If peresolimab worked in MS”…it is a check point inhibitor and could make MS worse if it is is immune mediated…however there are people with MS and cancer and MS and PML who may get checkpoint inhibitors….they also inhibit B cell activity as checkpoint inhibitors influence COVID-19 vaccines…
Alemtuzumab and AHSCT are superior….Come on Sweden publish atrophy data when treated at onset and ive rituximab…
Of course T and B cells do not work in isolation but a T cell immunologist can say it has everything to do with T cells and ignore B cells…it is harder to say the same stuff another way round.
Trogocytosis is an active process, in which one cell extracts the cell fragment from another cell, leading to the transfer of cell surface molecules, together with membrane fragments.
https://www.mdpi.com/2073-4409/10/5/1255#
Thanks
TA
I was NEIDA on (T) Natalizumab and am NEIDA on (B) Ocrelizumab.
My memory is proven worse each time its clinically tested. On a daily basis I keep trying to deal with it. Im 44 and sometimes its like I have some kind of Alzheimer or something. Knock on wood!
Arghhh 🤯
Forgive me but MS is really making it difficult for me lately cognitively… So you have to dumb this down for me… Is it that They won’t do further studies or think the findings are significant because it did not show the same % of reduction than a bcell depleter? Because no one will fund it due to not producing an immediate trophie or blue ribbon? 🤦♀️ Patience is a virtue or so I’m told. Like I commented in another post, I believe it’s all the the minute details.. a customized plan of balancing both tcell and bcells without over (or under)loading each individual patient. What is not enough for 1 person may be too toxic for another. So we all need personalized treatment plans that balance the ying and yang of all our b, c, and the rest of the alphabet soup of cells involved.
I guess the answer to your question is konw to the manufacturers
(a) They won’t do further studies (I dont know what the plans are)
or (b) think the findings are significant because it did not show the same % of reduction than a b cell depleter? (I am sure they think it is great as there is a company that has been developed to develop the apporach. They no doubt need investors to take this forward but perhaps the French Government will support the compnay)
(c) Because no one will fund it due to not producing an immediate trophie or blue ribbon? ….I think this is a possibility but let’s see what they do.
Yes personalised treatment is the mantra…but it would make it expensive