ProfK has many talents, but I bet you didn’t know he is a keen angler.
Now, you won’t find him in Clarme Common with his tackle out at the fish pond…which is a good thing as there are laws against that sort of behaviour :-), but as a card-carrying veggie, you wouldn’t have thought that he likes to fish…… for mice.
But that is just what has happened. The new bait is not a maggot or a carrot but a “tweet”. He knows the mice will bite and I’m afraid I have got netted.
So what’s this all about?
To refresh your memory in you can’t remember, we got the CARE-MS trial phase III data by a freedom of information request. Looking at the stuff from 2012 that they didn’t publish, we found a few things
Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K. JAMA Neurol. 2017;74(8):961-969. (It’s open access have a read)
As such we suggested that the memory B cells go down and could be important for MS and the CD4 T regulatory cell population goes down and CD8 suppressors do down. We also speculated that the hyper proliferation of immature B cells in the absence of T cell regulation may promote the environment for (a) autoimmunity and (b) a marked anti-drug response.
We asked the manufacturer for data on memory B cells and disease activity and for anti-drug responses and disease activity. Clinical trials data request.com enquiry 1867. What did we get?…. Well nothing but a telecom. It seems that the manufacturer has gone out of their way to try and discredit both ideas, to say that anti-drug responses are unimportant ECTRIMS 2018 (Jacobs et al, 2018) wonder if this will be published) and that depletion of T regs have no relationship to autoimmunity in this new study. The big names just don’t know what’s happening. However, I bet the Guys and Gals from Cambridge ask whats new here “we reported this years ago”
So now we have this paper that is the scientific carrot for the mischievous mice, that ProfK has gone fishing with.
What do I make of this?
Well I am very happy that the writers…..I mean Prof Weindl and the Care MS investigators has been able to reproduce our figures. I must admit I can’t remember any on the lead authors on this paper being on the teleconference to explain the data, except ProfG who was sat with me and ProfK, when we were told about this by David Margolis and Joanne Kaplan back in 2018 in response to our requests for data. It has taken a year for it to surface in this new incarnation.
Well what does this paper report say?
Of the 802 patients, 447 (56%) developed autoimmune adverse events.
It also says as we did in 2017 that memory CD4 and CD8 T cells are depleted, memory B cells are depleted and CD4 and CD8 T regulatory cells are depleted.
Therefore, it says the current European Label is wrong and therefore perhaps misleading. I guess this is being changed to reflect the new EMA recommendation, so perhaps a golden opportunity to change this. So the authors can be thanked for this.
On (pg 15) it say “The mechanism by which LEMTRADA exerts its therapeutic effects in MS is not fully elucidated. However, research suggests immunomodulatory effects through the depletion and repopulation of lymphocytes, including: – Alterations in the number, proportions, and properties of some lymphocyte subsets post-treatment – Increased representation of regulatory T cell subsets (WRONG. They are decreased) – Increased representation of memory T- (WRONG. They are decreased) and B-lymphocytes (WRONG. They are decreased)– Transient effects on components of innate immunity (i.e., neutrophils, macrophages, NK cells) The reduction in the level of circulating B and T cells by LEMTRADA and subsequent repopulation, may reduce the potential for relapse, which ultimately delays disease progression”.
So in this study they compiled the data from CARE MS I and II.
We only got CARE MS I and bits of CARE-MSII. After we published our paper in 2017, we still continued to get the data from the EMA in dribs and drabs . This came over a period of about two years. Thousands and thousands of pages each redacted to hide signatures and names….but sadly I have to say that when you turn pages of the pdf the black boxes would appear a fraction of a second late, so often it could be read, if interested. We weren’t interested. Indeed we weren’t interested in much of that sent. But as they will supply redacted data, I guess this must be remembered. Eventually we told the EMA to stop as we felt sorry for the poor sod doing the redaction. We couldn’t put them through two more years of wasting their time with CARE-MS II. I have often wondered if it was the EMA doing the redaction or someone at Sanofi. When we got the Merck data we got the lot in one day, but they weren’t interested in the drug at the time. I guess it should be a lesson on how to write the reports. Personally I think companies should have to deposit this data to get a licence, so that it can be interogated.
Anyway they have looked at the peripheral cell numbers and asked if this relates to disease activity ir autoimmunity over six years. The answer is no.
The paper sort of says that it a waste of time looking in the blood for indicators of autoimmunity and disease activity in people taking alemtuzumab. I will takes bets that some or all of the authors will continue to look in the blood of people with MS for just this. Should we ask, why would they do this if they really think it is not an informative place to look? However, as I saw this is not new, (uncited) studies from Cambridge published years ago said the same thing, so it would be a surprise if they found something different.
Now I will say I am disappointed that they find nothing in relation to memory B cells
However, this is a bit like asking if you tread on some dog poop with a hole in your shoe, whether you will have new shoes five years later. We have all got new shoes five years later whether your trod on dog dirt or not. However, you can bet those shoes went in the bin 5 minutes after the squelsh and that you were off to Freeman Hardy and Willis for a new pair the next day.
So if you don’t look in the right place or in the right way you are not going to find anything. What happens to a cell today is not going to tell you much about effects 5 years on. If we see peaks in cell numbers it may not be disease activity, but may be that you have an infection.
I accept and indeed will be showing that lyphocyte depletion levels do not relate to disease activity, so I have no problem with this.
Now even if you accept the possibility that depletion of B and suppressor T cells predispose to MS and then ask the question does a person with cancer who takes alemtuzumab get autoimmunity?, The answer is no they don’t get autoimmunity, because it is something about the genetics of MS that is important (or the dose), but they all deplete B and suppressor T cells in cancer just like occurs in MS. Ask the question is there anyone that did not deplete regulatory cells and showed a B cell repopulation that did not get autoimunity and then you may disprove our idea.
The many authors are credited with critical review. I wonder if any on them asked what happened at the individual level, maybe that may tell us something. Anyway, I will be writing to the author to ask for the individual data as they say ” Qualified researchers may request access to patient-level data and related study documents” hopefully this will arrive as it didn’t when I asked back in Novemeber 2017….maybe I’m not qualified:-(
Importantly, the down side of the view that peripheral blood numbers are unimportant means that neuros are not looking at lymphocyte levels when they use alemtuzumab.
So if you are on alemtuzumab, please, please, please ask to see what your lymphocyte levels are before and after each infusion (one month on either side). Neuros may be too busy to check this out. Whilst it may well be the case that lymphocyte levels can-not predict if your disease will activate or not, after all it will be a tiny subset of cells that are important. However, please remember this. If it is not depleting, it is probably not working. If you are one of these individuals then you may indeed be at risk of treatment failure and you and your neurologist need to be extra vigilant and you may need to respond if there is disease breakthrough or respond to stop this happening.
Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab. Wiendl H, Carraro M, Comi G, Izquierdo G, Kim HJ, Sharrack B, Tornatore C, Daizadeh N, Chung L, Jacobs AK, Hogan RJ, Wychowski LV, Van Wijmeersch B; CARE-MS I, CARE-MS II, and CAMMS03409 Investigators. Neurol Neuroimmunol Neuroinflamm. 2019;7(1).
OBJECTIVE: To examine the association between peripheral blood lymphocyte pharmacodynamics and autoimmune adverse events (AEs) or return of disease activity in alemtuzumab-treated patients with relapsing-remitting MS.
METHODS: Patients received 2 alemtuzumab courses (12 mg/d IV; 5 days at baseline, 3 days 12 months later) in the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis studies (NCT00530348 and NCT00548405) and could then receive as-needed alemtuzumab or other disease-modifying therapy in a 4-year extension (NCT00930553). Lymphocytes were phenotyped quarterly over 2 years using fluorescence-activated cell sorting. Pharmacodynamic assessments included counts of total lymphocytes, CD3+ T cells, CD4+/CD8+ T cells (total/naive/memory/regulatory [Treg]), and CD19+ B cells (total/immature/mature/memory) and ratios of CD19+ (total/immature/mature/memory) to Treg (CD4+/CD8+) counts. Assessed autoimmune AEs included immune thrombocytopenia, nephropathies, and thyroid events. Efficacy assessments included relapses, 6-month confirmed disability worsening (CDW), and MRI disease activity.
RESULTS: Lymphocyte repopulation patterns, including ratios between distinct lymphocyte subsets (e.g., CD19+ to Treg cell count ratios), showed no significant differences over 2 years in patients developing/not developing autoimmune AEs, relapses, CDW, or MRI activity through 6 years following alemtuzumab. Lymphocyte kinetics were also unrelated to multiple autoimmune AEs or extreme clinical phenotypes.
CONCLUSIONS:Repopulation kinetics of the evaluated peripheral lymphocyte subsets did not predict autoimmune AE occurrence or disease activity, including return of disease activity after 2 alemtuzumab courses. Further study is needed to investigate potential antigen-level markers of treatment response.