David Baker; Samuel S. Herrod, Cesar Alvarez-Gonzalez, Gavin Giovannoni; Klaus Schmierer Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurol. Published online June 12, 2017. doi:10.1001/jamaneurol.2017.0676
IMPORTANCE Alemtuzumab, a CD52-depleting monoclonal antibody, effectively inhibits relapsing multiple sclerosis (MS) but is associated with a high incidence of secondary B-cell autoimmunities that limit use. These effects may be avoided through control of B-cell hyperproliferation.
OBJECTIVE To investigate whether the data describing the effect of alemtuzumab on lymphocyte subsets collected during the phase 3 trial program reveal mechanisms explaining efficacy and the risk for secondary autoimmunity with treatment of MS.
DESIGN, SETTING, AND PARTICIPANTS Lymphocyte reconstitution data from regulatory submissions of the pivotal Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I and II (CARE-MS I and II) trials were obtained from the European Medicines Agency via Freedom of Information requests. Data used in this study were reported from June 22 to October 12, 2016.
MAIN OUTCOMES AND MEASURES Tabulated data from T- and B-lymphocyte subset analysis and antidrug antibody responses were extracted from the supplied documents.
RESULTS Alemtuzumab depleted CD4+ T cells by more than 95%, including regulatory cells (−80%) and CD8+ T cells (>80% depletion), which remained well below reference levels throughout the trials. However, although CD19+ B cells were initially also depleted (>85%), marked (180% increase) hyper-repopulation of immature B cells occurred with conversion to mature B cells over time. These lymphocyte kinetics were associated with rapid development of alemtuzumab-binding and -neutralizing antibodies and subsequent occurrence of secondary B-cell autoimmunity. Hyperrepopulation of B cells masked a marked, long-term depletion of CD19+ memory B cells that may underpin efficacy in MS.
CONCLUSIONS AND RELEVANCE Although blockade of memory T and B cells may limit MS, rapid CD19+ B-cell subset repopulation in the absence of effective T-cell regulation has implications for the safety and efficacy of alemtuzumab. Controlling B-cell proliferation until T-cell regulation recovers may limit secondary autoimmunity, which does not occur with other B-cell–depleting agents.
- You have to read the data, not someone’s interpretation of the data, as that may be wrong.
- Base your assumptions on absolute numbers not percentages
- Serious misinterpretation of data can be made, when basing ideas on percentage change
You complained you didn’t have a real example so here it is.
I does probably not mean anything in relation to your treatment, but is does to the interpretation of your treatment
Therefore it makes you think that wouldn’t it be great if our mechanism of action is associated with an increase in T regulatory function.
You make do your experiments to prove that your drug works by increasing T reg cells.
Don’t believe me. Have a read of most current EAE papers. Is there a dissenting voice….not really, because they would get their paper rejected:-(.
Cox AL, Thompson SA, Jones JL, Robertson VH, Hale G, Waldmann H, Compston DA, Coles AJ. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol. 2005; 35:3332-42.
Zhang X, Tao Y, Chopra M, Ahn M, Marcus KL, Choudhary N, Zhu H, Markovic-Plese S. Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis. J Immunol. 2013; 191:5867-74.
Abstract “CD4(+)CD25(+)CD127(low) regulatory T cells preferentially expanded within the CD4(+) lymphocytes, reaching their peak expansion at month 1” …from n=10
Here’s another one
De Mercanti S, Rolla S, Cucci A, Bardina V, Cocco E, Vladic A, Soldo-Butkovic S, Habek M, Adamec I, Horakova D, Annovazzi P, Novelli F, Durelli L, Clerico M. Alemtuzumab long-term immunologic effect: Treg suppressor function increases up to 24 months. Neurol Neuroimmunol Neuroinflamm. 2016 ;3(1):e194.
Also said “A significant increase in Treg cell percentage was observed at month 24 and was accompanied by an increase in Treg cell suppressive activity against MBP-specific Th1 and Th17 cells”.
Havari E, Turner MJ, Campos-Rivera J, Shankara S, Nguyen TH, Roberts B, Siders W, Kaplan JM.Impact of alemtuzumab treatment on the survival and function of human regulatory T cells in vitro. Immunology. 2014;141(1):123-31.
Freedman MS, Kaplan JM, Markovic-Plese S. Insights into the Mechanisms of the Therapeutic Efficacy of Alemtuzumab in Multiple Sclerosis. J Clin Cell Immunol. 2013 Jul 8;4(4).
“Tregs (i.e., CD4+CD25high), were significantly over-represented for the first 6 months after alemtuzumab treatment, even though the proportion of Tregs to total CD4+ T cells was similar in MS patients and healthy controls prior to treatment.”
Don’t believe it?
This is why MS is inhibited. QED. I think this maybe right but not because of this data
So it all works great, if you think MS is a T cell issue, Treg cells outnumber the T cells, MS is stopped. However at 12 months after treatment they are back to normal and the T cells are still wiped out of existence for another 12 months or more. So when the T regs surge there are no pathogenic cells to regulate they are gone for a few years. So this idea doesn’t hold much water
But what if there is a B cell problem?
then perhaps your ideas are up s**t creek without a paddle:-(
Base your assumptions on absolute numbers not percentages.
Bonzoforgot (one of the readers LOL)…go get your calculator so we can work this one out:-). However, hope you can do the important bit without one.
There are about 850-900 CD4 cells per microlitre at baseline (first point in graph above on the left ), So if there 3.7% CD4, CD25 T reg (according to the comment above) then there 3.7% of 850,000 cells/mL = 31,450 cells/mL.
So in Health about 30,000 T regs per millilitre (a thousandth of a litre of blood)
The numbers are different but the percentages are consistent with the CARE MS I (findings below). However, I think the point is made, there it is a very, very significant decrease.
CARE-MS 1 data from EMA
This is what we found when we looked at the trial data results
Luckily in the phase III trial data the inferences are based on more
This latter question was thought about and dismissed
Joanne L. Jones, Chia-Ling Phuah, Amanda L. Cox, Sara A. Thompson, Maria Ban, Jacqueline Shawcross, Amie Walton, Stephen J. Sawcer, Alastair Compston, and Alasdair J. Coles. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H)
“We have previously disproved the…..possibility: in the context of multiple sclerosis treatment by alemtuzumab, CD4+CD25hi Tregs and lymphocyte FoxP3 expression are both increased for 6 months after treatment…“
If you get this, we can start to understand how alemtuzumab works and why it may cause autoimmune side effects.
More next time.