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Greetings and welcome to EHA 
Unplugged, the official podcast 

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channel of the European 
Hematology Association EHA. 

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So today I would like to welcome
Dominic Wolf. 

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He is from the Medical 
University of Innsbruck in 

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Austria, and he's an expert in 
the immune system in MD's. 

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So we're going to talk a little 
bit about targeting the immune 

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system in MD's. 
So welcome, Dominique, It's nice

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that you could join us. 
I mean, we all know that 

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transplantation works in MD's, 
right? 

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And in essence, this is actually
using the immune system to 

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targeting MD's. 
So. 

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So why do you think it works? 
I think so. 

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First of all, thank you for the 
invitation. 

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Great to be here. 
And yeah, allotransplantation is

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the prototype of immunotherapy 
for hematological diseases, 

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which we all use for since 
decades. 

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And then we all like it on one 
hand, but also we all dislike it

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on the other hand, because it's,
it's, it's saved life. 

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It saves a lot of lives also for
particularly high risk MD's 

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patients, but also it, it harms 
patients due to its toxicities 

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in terms of non relapse related 
toxicities, which is one of the 

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major limitations. 
And there's a lot of 

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advancement, but it's still a 
big problem in in daily clinical

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practice, particularly in GVHD 
management and all that stuff. 

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I'm personally quite convinced 
due to the long experia I have 

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myself in transplantation of 
MD's patients and also AMI 

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patients that it's indeed that 
the long term success of the of 

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the technology indeed very much 
depends on the graft versus 

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disease effect. 
Because you can, you can really 

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nicely see also with the new 
methods of of sensing relapses 

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by by molecular markers in 
patients after transplantation. 

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When you then withdraw, for 
example, or reduce 

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immunosuppression or you even 
give donor lymphocytes as, as 

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you know, weapons fostering the 
graftus leukemia effect, you can

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really often see that you can 
again go back to MRD negativity 

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and reduce long term control of 
the disease. 

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So in addition to just being a 
replacement therapy, the 

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lymphocytic compartment, but 
also the NK compartment in the 

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graft is definitely centrally 
involved in controlling the 

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disease. 
But as I said, it's also the 

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major limitation called those 
cells can also do do harm the, 

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the, the recipients by inducing 
severe life threatening or 

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inducing a lot of morbidity 
burden in patients with, with 

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acute and, and in particularly 
chronic GVHD. 

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And it's interesting the also 
there, there's a lot of large 

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big data, big file analysis from
EBMT showing that you have a 

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nice correlation of, you know, 
chronic GVHD and Disease 

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Control. 
So you can't definitely spread 

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those two, you know, the one 
which is the therapeutic effect,

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meaning graft versus leukemia 
and the one which is the, let's 

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say, side effect, the graft 
versus host disease. 

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It's it's, it's somehow also 
linked. 

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And I think it's still very 
important. 

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We need this kind of therapy. 
I just came back from my round 

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here. 
We have a young lady, same age, 

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young like, you know, young, 
same age. 

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I have not very young 
middle-aged, but you know, 

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having high risk MD's and it's, 
it's, it's clear we have to go 

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for donor search and then go 
for, for transplantation finally

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to, to cure the disease. 
Because not still we don't have 

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alternatives by using the immune
immune system, for example cat T

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cells or other immunotherapies 
being being a curative 

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alternative for this patient 
population. 

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But I also think you know this, 
this brings me to a little bit, 

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I mean back to to earlier stages
of MD's where we know a lot of 

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things are happening in the 
immune system. 

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Why do you think, what do you 
think would be good targets or 

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what have you have shown to be 
good targets and why they're not

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good enough? 
Can you comment a little bit on 

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that? 
Yeah, For me, the, the lower 

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risk MD's patients are a 
beautiful prototype of how 

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myeloid, the myeloid compartment
induces inflammatory circuits, 

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which is very important for the 
microenvironment in the bone 

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marrow, meaning the also the 
differentiation capacity of 

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cells and, and, but, but which 
can also induce in in patients. 

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You know, all of, of, of you, 
you, you, you take care of, of 

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MD's patients and you know, 
these patients which have 

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inflammatory symptoms in 
addition to their MD's and some 

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patients do not have any signs 
of, of inflammatory side effects

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and, and others can have really 
severe hyperinflammatory 

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syndromes. 
I'm not talking about VEXAS, 

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which is a very specific subtype
of, of a very defined mutation. 

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I'm talking about really the 
classical MD's having the, the 

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morphological MD's having also 
the mutational pattern and you 

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know, these patients having 
inflammatory symptoms. 

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And I think here we we are 
currently learning more and more

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how genetics in the minded 
compartment compartment imprint 

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in eight immune signaling, which
finally leads to 

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hyperinflammation to production 
of for example, Illinois one and

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Illinois 18 HMGB 1 as a, you 
know, final readout of 

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activation of in of the Nile 3 
inflammasome. 

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Or we can also see activation of
intracellular protein complexes 

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which are lowering the threshold
of the TLR activation signals. 

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And there are many TLRS out out 
there which are usually 

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recognizing danger signals such 
As for example, APS from gram 

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negative negative bugs. 
And if you have mutations which 

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affect these intracellular 
adapter complexes, which make 

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signaling more likely in, in, in
when the cells are exposed, for 

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example, to to TLR activating 
sickness by LP's or there can 

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also be other poor inflammatory 
stimuli which activate the 

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cells. 
You finally get 

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hyperinflammation, which is 
where you can then see in 

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patients, neutrophilic 
dermatosis, fever requiring 

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steroids, arthritis and all this
stuff which we, which we, we can

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see in clinics. 
And there are many studies out 

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there trying to, you know, from 
understanding the basic biology 

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of what's going on in the cells,
trying to transfer this to, to 

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clinical concepts. 
One concept is trying in low 

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risk MD's to inhibit the knife 
three I 1 axis by Kanakinomap, 

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for example. 
Also there are, you know, I have

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been for for seven years at at 
Bonn University and there's one 

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of the leading knife 3 
researchers. 

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I kill lots and we are 
collaborating a lot and IK has 

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developed for example knife 3 
inhibitors developed in a spin 

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off now taking over by by a 
large pharma company. 

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So. 
This is not in clinical trials 

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yet or. 
It's it's, it's just going into 

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into phase one, but just showing
you that knife 3 inhibit 

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inhibition is in addition, you 
know, is more upstream to, to to

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to inhibiting I-1. 
So this this could be for the 

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future. 
And these are the concepts 

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trying to interfere with the 
knife 3 I-1 caspase one I one 

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access. 
Also when you inhibit when you 

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inhibit night 3, you could be 
more if efficient or this could 

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could be a more efficient 
approach to to inhibit induction

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of pyroptosis which very much 
correlates to the 

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differentiation defects and low 
risk MD's and which is mainly 

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mediated by night 3 induced 
activation of caspase 1. 

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And how do you see, because I 
think you know with there's the 

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inflammation in the 
microenvironment and then 

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there's the inflammation in the 
myeloid cells in the clone. 

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So, so how do you see this 
interaction? 

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Is the one dependent on the 
other or are you inhibiting both

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the microenvironment and the 
clone or? 

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I think we need to target both. 
It's a very good point you 

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mentioned because it's always 
like a chimera in the bone 

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marrow. 
You have the diseased clonal 

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cells and you have the non 
diseased cells. 

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And I think we can learn a lot 
from from the story of MPNS 

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because at the beginning we 
thought, okay, it's the Jack 2 

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mutant cells where we have to 
inhibit Jack 2. 

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And finally, particularly on a 
basis on a beautiful work from 

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Ross Levine, we have learned 
that inhibition of Jack two in 

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the non clonal compartment is 
very much involved in also 

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affecting the clonal expansion. 
So it's, you know, those cells 

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always interact. 
There's the clonal cell which 

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has a genetic event which 
produces cytokine and the other 

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one responds to this thing also 
to the to the the the danger 

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patterns in the microenvironment
in the bone marrow and they all 

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it's it's like a full year dirt.
So it's it's the non cloning 

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cloning compartment. 
Probably we have to target them 

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both of them, but we are not 
there that we understand the 

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mechanisms in that detail. 
And I think also based on the on

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the development of single cell 
technologies, for example, we 

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are currently establishing a 
technology, we are doing a lot 

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of single cell sequencing work 
and we, we, we develop a so 

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transcriptomic sequencing, but 
we, we need to annotate when you

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have, when we have a single 
transcriptome, the whole 

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transcriptome of a single cell, 
I need to know the genetic 

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background of this cell. 
And particularly in the 

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hematology where you have 
different clones having one 

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mutation 1 plus the other 
mutation and cells which are non

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mutated normal hematocritic 
cells, we need to understand so 

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which pathways are really 
induced there to really more or 

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deliver develop more more 
targeted approaches on the basis

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of anti-inflammatory treatment. 
But I think my three I one is 1 

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possibility which is very 
interesting in in low risk and 

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years where the differentiation 
problem, the cytopenia is the 

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main problem. 
Yeah. 

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Another, another development is,
is, is, is is targeting the the 

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Mighty 88 complex where Iracs 
are essential in, in, in the 

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signalling complex. 
And that's the one we know from 

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the lymphoid diseases, right? 
Yes, exactly. 

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That's the one we know from from
lymphoma and from widen sperm 

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disease. 
It's it's mighty 888 mutations. 

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But here we have different kind.
It's not the classical Mighty 88

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mutated activation of the Mighty
88 complex. 

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It's rather based on proteins 
which are part of the complex 

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and Iracs play an essential role
in the normal Mighty 88 induced 

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ELR signalling transduction into
the cell leading to the output 

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of producing cytokines. 
For example, you know normal 

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cell response to APS in in a 
sepsis and bacteria exposure. 

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And here we have based on 
spliceosome mutations, IRAC can 

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be differentially spliced and 
then we have an overabundance of

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the long form of Iraq four. 
And this, this long form of Iraq

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4 leads to, to a hyperactivation
of this complex and this Iraq 

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inhibitors are clinically 
tested. 

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There is some data out there. 
It, it seems promising, but it's

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very early. 
And you know, the basic idea is 

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also to, to trying to, to 
interfere with this inflammatory

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signalling circuit in, in, in, 
in MD's. 

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And do you think this is even 
part of the whole I mean the the

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the way that this arises, you 
know, when you go from from 

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cheap or sequence to MDSI mean 
this is is this driven by 

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inflammation, you think, or is 
it is it the what do you? 

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And is it mutation to different 
types of mutation also or how 

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do? 
You, it's a very good question. 

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I mean, I think it's, I think I 
mean everybody or it's, it's, 

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let's say it's, it's, it's 
accepted that chronic 

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inflammation leads to loss 
production and chronic local 

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stress of hematopoietic cells. 
And I could envision that 

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chronic inflammation also 
induces the cloner development 

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or clonal development or clonal 
expansion of, of, of, of chip 

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clones, then leading by somehow 
having hyper proliferative 

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features leading to secondary 
genetic events, really finally 

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ending up in a, in a dysplasia 
coming from, you know, normal 

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hematopoietic output from clonal
hematopoiesis, perhaps going 

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over C cast and really going to 
dysplasia, which may be at least

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in some patients very much 
depend on on induction of 

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pyoptosis by activation of the 
I-1 pathway. 

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But I'm, I'm not so sure 
whether, because Chip is so 

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frequent and, and I'm not so 
sure whether this is the only, 

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whether the, the inflammation in
the Chip clone itself is the 

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only driving force. 
I think it very it could be that

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that there are other 
inflammatory external micro 

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environmental driven forces. 
And I think there's a beautiful 

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model coming from lung cancer 
where, you know, Charlie Swanton

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has just recently published this
air pollutant paper where they 

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show that in in the lung we 
have, you know, let's say the 

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lung chip is the GFR mutation in
the epithelial cells. 

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But then then you have the 
microparticle dust exposure 

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which induces like green 
flamosome in myeloid cells, 

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particularly macrophages. 
And this inflammatory stress by 

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the air pollutants induces then 
the transformation and then the 

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CARAS mutation comes on top and 
then you see the transformation.

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And they have really shown 
beautifully that EGFR mutated 

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lung cancer is, is directly 
correlating to the, to the 

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microparticle exposure. 
When you look at, you know, the 

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big cities in, in, in Asia that 
the, the, the, and you compare 

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this to probably, let's say one 
of our side values here. 

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It's, it's, it's really a 
highly, a highly correlated 

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observation. 
And I think we could, it could 

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be that we have the same model 
here. 

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We have a spontaneous 
age-related sensitivity of 

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hematopoietic cells to to get a 
chip lesion. 

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And then we have external 
factors. 

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There was a recent paper showing
that for example, Adipositus is 

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driving clonal expansion of chip
clones in a, in a, in a nice 

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mirror and model. 
So this, I think it's a it's a 

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very complex mixture, but it's 
for me, it's hot topic because 

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it. 
So do you think we can prevent 

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MD's progression? 
Yeah, Perhaps we can prevent and

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progression by by being 
efficiently, more efficiently 

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having anti clonal therapies. 
I think we have to reduce the 

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clonal size and we have to 
reduce inflammation, 

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anti-inflammatory and anti 
clonal. 

247
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And it's a bit like when you go 
to MPN, it's a different field. 

248
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But conceptually you can induce 
anti clonal therapy with 

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interferon. 
It's an and you can be very 

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perfectly anti-inflammatory with
drug inhibitors, but you don't 

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have this very, very strong anti
clonal drugs in, in, in, in, in,

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in low risk MD's because we 
can't, you know, interferon is 

253
00:15:39,160 --> 00:15:41,800
not, is not a good idea in this 
setting. 

254
00:15:41,800 --> 00:15:45,280
But conceptually I think it it 
it that would be interesting. 

255
00:15:45,880 --> 00:15:49,080
So, so, so is this because we 
actually don't have anything 

256
00:15:49,080 --> 00:15:51,000
that reduces the clone and lower
risk? 

257
00:15:51,000 --> 00:15:53,800
And yes. 
Yes, we, we, we could perhaps 

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reduce the clone by, by, by 
ADSAP, but but we don't use it 

259
00:15:58,200 --> 00:16:00,960
in this sense. 
We would rather try to to 

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reinforce blood production by by
growth factors or lose, Batter 

261
00:16:05,840 --> 00:16:07,960
said. 
Which is also some kind of, you 

262
00:16:07,960 --> 00:16:09,960
know. 
There was an interesting talk by

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00:16:09,960 --> 00:16:13,880
Valier Santini on at the SA 
showing that Emitlestat could 

264
00:16:13,880 --> 00:16:17,960
actually reduce the clones, but 
I don't that was that was sort 

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00:16:17,960 --> 00:16:21,280
of for me a completely new 
discovery I think. 

266
00:16:21,880 --> 00:16:24,080
Definitely. 
What about the, what about the 

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00:16:24,080 --> 00:16:25,560
adaptive immune system does 
that? 

268
00:16:26,160 --> 00:16:28,800
I mean people have been trying 
to target that in MD's. 

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What do you think about that? 
Very difficult data are not 

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00:16:31,880 --> 00:16:34,320
convincing. 
We don't have the right targets.

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We don't understand the targets 
when when it comes, for example,

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00:16:37,920 --> 00:16:40,560
to checkpoint inhibitors, there 
are many, many trials, but the 

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00:16:40,560 --> 00:16:43,520
data is disappointing. 
The only check inhibitors which 

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which which which seems to be 
interesting. 

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00:16:46,200 --> 00:16:49,480
I mean, Neil Davis has published
in the May issue of of JC or for

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00:16:49,480 --> 00:16:52,320
example, the combination of 
macro Mac olimab together with 

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00:16:52,320 --> 00:16:55,880
other cited in, in, in in high 
risk, higher risk MD's patients.

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00:16:56,160 --> 00:16:59,240
So I think these the, the, the, 
the myeloid checkpoints seem to 

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be more interesting. 
The team three data are a bit 

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00:17:02,120 --> 00:17:04,240
disappointing. 
The stimulus first stimulus 

281
00:17:04,240 --> 00:17:07,359
Phase 2 is a bit disappointing. 
But let's see what's what's 

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00:17:07,359 --> 00:17:09,599
coming out there in the, in the 
randomized phase three. 

283
00:17:09,760 --> 00:17:13,040
I think we have to dig deeper 
and probably it's also due to 

284
00:17:13,040 --> 00:17:17,079
the complexity of the of the 
disease, the all Comer studies 

285
00:17:17,079 --> 00:17:22,640
with these kind of approaches 
very likely not to be positive. 

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00:17:22,640 --> 00:17:25,920
So I think we need to understand
the basic biology better to more

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00:17:26,119 --> 00:17:28,840
to better preselect patients, 
which are probably the ones 

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00:17:28,840 --> 00:17:32,600
which select, for example, from 
Macoli MAP or from Tim 3 

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00:17:32,600 --> 00:17:34,520
antibodies. 
Or perhaps there are even some 

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00:17:34,520 --> 00:17:40,440
of them which may be sensitive 
to, to, to, to classical 

291
00:17:40,440 --> 00:17:42,960
checkpoint inhibitors such as 
EPILIMO MAP or NIBO. 

292
00:17:43,200 --> 00:17:46,120
But actually in the in, in, in 
the study so far, the signals 

293
00:17:46,120 --> 00:17:48,920
are not very strong. 
The signals for macolimab are 

294
00:17:48,920 --> 00:17:51,080
strong. 
I mean, the C, the CR rate is 

295
00:17:51,400 --> 00:17:55,200
something between 3540%. 
The overall response rate is 

296
00:17:55,200 --> 00:17:58,400
good. 
The TP 53 mutants seem to be 

297
00:17:58,400 --> 00:18:00,960
very encouraging. 
And even if you and if you then 

298
00:18:00,960 --> 00:18:04,120
go to transplant, the data looks
quite interesting. 

299
00:18:04,120 --> 00:18:07,320
So I think it's early, but it's 
a very good and interesting 

300
00:18:07,320 --> 00:18:08,720
approach. 
Yeah. 

301
00:18:08,720 --> 00:18:11,080
And probably that's probably one
of the very few things we've 

302
00:18:11,080 --> 00:18:13,800
seen working in TP53 Muted 
definitely. 

303
00:18:14,160 --> 00:18:17,200
And of course also if we go more
to the experimental side, what 

304
00:18:17,200 --> 00:18:20,880
about cut teas in in MD's AML? 
Do you think that will have, I 

305
00:18:22,080 --> 00:18:23,840
think that will have a role or? 
Yeah. 

306
00:18:24,080 --> 00:18:30,160
One problem is the target, yeah,
it's a hematopoietic derived 

307
00:18:30,160 --> 00:18:31,720
hematopoietic stem cell derived 
disease. 

308
00:18:31,720 --> 00:18:34,600
So the the targets are often 
shared with normal hematopoietic

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00:18:34,600 --> 00:18:36,800
stem cells. 
I mean, we all know the the 

310
00:18:36,800 --> 00:18:42,880
paper from 218 published in cell
in, in, in, in, in monkeys and 

311
00:18:42,880 --> 00:18:46,080
in preclinical models that that 
you can combine stem cell 

312
00:18:46,080 --> 00:18:53,920
transplantation, taking out the 
the 33 by by and transplant the 

313
00:18:53,920 --> 00:18:56,960
stem cells without the target 
together with the T cells 

314
00:18:56,960 --> 00:18:58,840
targeting the target on the 
myeloid cells. 

315
00:18:58,840 --> 00:19:06,160
But I think it's a very complex 
setting and the appropriate 

316
00:19:06,160 --> 00:19:08,920
targets are currently really 
lacking. 

317
00:19:09,480 --> 00:19:14,960
There are early clinical trials 
of, of technologies trying not 

318
00:19:14,960 --> 00:19:18,920
to use CAR T cells which already
have the, the, the single chain 

319
00:19:19,120 --> 00:19:22,880
bound to the transplant domain. 
So that you, if you, if you 

320
00:19:22,880 --> 00:19:26,760
infuse the CAR T cell that it 
goes directly to, to, to the 

321
00:19:26,760 --> 00:19:29,680
targets on the Myelo cells, but 
also on the, on the healthy 

322
00:19:29,680 --> 00:19:33,880
cells, but then use adapters. 
So you have a CAR T cell which 

323
00:19:33,880 --> 00:19:38,000
is somehow cold and you have, 
for example, a leucine SIPA. 

324
00:19:38,000 --> 00:19:41,320
And then you give a we have a 
drug which on one hand side 

325
00:19:41,400 --> 00:19:44,880
targets the myeloid target and 
on the other hand side you can 

326
00:19:45,160 --> 00:19:47,840
you it, it binds to the to the 
cold CAR T cell. 

327
00:19:47,840 --> 00:19:51,720
But you can compete with these 
small drugs when they induce 

328
00:19:51,720 --> 00:19:56,880
toxicity such as CVS CIS, but 
also perhaps inducing a 

329
00:19:56,880 --> 00:20:00,160
pleasure. 
But I think addressing and and 

330
00:20:00,160 --> 00:20:03,520
identification of of the of the 
most appropriate targets is is 

331
00:20:03,520 --> 00:20:06,920
one of the. 
Biggest problems we, we, we have

332
00:20:06,920 --> 00:20:10,160
not only in, in, in myeloid 
diseases, also in T cell 

333
00:20:10,160 --> 00:20:12,520
lymphomas, for example, where 
everybody, you know, it's so 

334
00:20:12,520 --> 00:20:16,120
hard to treat, so difficult and,
and no CAR T cell therapy 

335
00:20:16,120 --> 00:20:18,440
available. 
It, it, it's, it's, it's a pity.

336
00:20:18,440 --> 00:20:21,840
And I think we have to to dig 
deeper there that, that there is

337
00:20:22,080 --> 00:20:25,520
early clinical trials on CAR T 
cells also in, in MD's patients,

338
00:20:25,520 --> 00:20:28,960
but it's definitely too early 
and it's, it's, it's far from 

339
00:20:28,960 --> 00:20:32,800
clinic to be honest. 
And isn't it also a problem that

340
00:20:32,920 --> 00:20:36,520
sort of MDI mean if you have an 
advanced MD's, almost all the 

341
00:20:36,520 --> 00:20:38,360
stem cells are part of the 
clone, right? 

342
00:20:38,360 --> 00:20:41,720
So, so will there be residual 
stem cells if we attack them? 

343
00:20:41,720 --> 00:20:45,320
We say it once, I don't know, 
you know, it's isn't that an 

344
00:20:45,320 --> 00:20:49,640
issue also that we almost need 
to have a transplantation on top

345
00:20:49,640 --> 00:20:50,920
or. 
Yeah. 

346
00:20:51,280 --> 00:20:54,000
And then you can ask, I mean, 
what is, what is then the net 

347
00:20:54,000 --> 00:20:57,800
benefit of of doing it when you 
anyhow have to go for for for a 

348
00:20:57,800 --> 00:21:00,000
chance? 
And it's probably. 

349
00:21:00,200 --> 00:21:02,840
Too healthy you don't have the 
possibility to have an 

350
00:21:02,840 --> 00:21:05,520
ontologist re grafting because 
you don't have healthy stem 

351
00:21:05,520 --> 00:21:08,560
cells. 
I think that for me in myeloid 

352
00:21:08,560 --> 00:21:13,560
diseases, alotransplantation 
will be in place for the next, 

353
00:21:14,000 --> 00:21:16,880
let's say at least for a decade.
Yeah. 

354
00:21:17,480 --> 00:21:21,320
I don't see the developments 
which can replace Aloe for high 

355
00:21:21,320 --> 00:21:25,000
risk MD's so far currently. 
You know, I more see the 

356
00:21:25,000 --> 00:21:28,440
anti-inflammatory potential in 
earlier lines of MD's and the 

357
00:21:28,440 --> 00:21:32,040
hyperinflammatory patients. 
But you know, in in high risk 

358
00:21:32,040 --> 00:21:35,480
MD's patients, I, I, I, I see 
transplantation in place for the

359
00:21:35,480 --> 00:21:38,480
next at least. 
So in the early phase is 

360
00:21:38,480 --> 00:21:40,760
actually more preventing 
progression and yeah, 

361
00:21:41,160 --> 00:21:42,160
definitely. 
Yeah. 

362
00:21:42,560 --> 00:21:45,360
And there we have to understand,
I mean we just recently finished

363
00:21:45,640 --> 00:21:49,560
a project where we collected 100
patients and we want to 

364
00:21:49,560 --> 00:21:52,320
understand because we know in 
lower risk MD's fatigue is a 

365
00:21:52,320 --> 00:21:53,560
strong. 
Yeah. 

366
00:21:54,120 --> 00:21:59,000
Strong driver of is is a 
prognostic factor and and why is

367
00:21:59,000 --> 00:22:01,640
that the case? 
What, what is fatigue really? 

368
00:22:01,640 --> 00:22:04,080
I mean, also in long COVID, what
is the fatigue? 

369
00:22:04,200 --> 00:22:06,920
I mean, is it is it subtle 
chronic inflammation? 

370
00:22:07,800 --> 00:22:11,160
And I think in in MD's we should
really trying to dissect and 

371
00:22:11,160 --> 00:22:15,600
bring together fatigue, which is
not a result of having a low 

372
00:22:15,600 --> 00:22:18,920
hemoglobin, it's a result of 
hyperinflammation probably. 

373
00:22:18,920 --> 00:22:21,600
And we have to understand which 
mutations to induce which 

374
00:22:21,600 --> 00:22:25,200
pattern of cytokines which then 
induces fatigue, which may also 

375
00:22:25,200 --> 00:22:29,240
drive the the the the the the 
more quick transformation to 

376
00:22:29,400 --> 00:22:33,800
over the AML then or which which
then is a is a potentially life 

377
00:22:33,800 --> 00:22:36,560
threatening situation. 
I think that's a very 

378
00:22:36,560 --> 00:22:38,960
interesting end point because 
this is also one that really 

379
00:22:38,960 --> 00:22:40,440
means a lot for the patients, 
right? 

380
00:22:40,440 --> 00:22:43,160
So, so do you think this 
inflammation is actually in the 

381
00:22:43,160 --> 00:22:46,840
central nervous system or, or 
how do you envision the 

382
00:22:46,840 --> 00:22:48,920
combination of inflammation and 
fatigue? 

383
00:22:49,480 --> 00:22:52,120
It could, it could be that it's,
it's a very good point that it's

384
00:22:52,120 --> 00:22:57,320
a, it's an inflammation which 
also effects the, the CNS and, 

385
00:22:57,320 --> 00:22:59,640
and thereby induces the mood 
symptoms. 

386
00:23:00,080 --> 00:23:02,840
But, but the problem is that we 
do not know. 

387
00:23:03,120 --> 00:23:06,240
We do nothing. 
We do know nothing about, you 

388
00:23:06,240 --> 00:23:08,960
know, the, the, the clonal 
composition of the, for example,

389
00:23:08,960 --> 00:23:11,880
the myeloid cells in the brain. 
Whether that takes, you know 

390
00:23:11,880 --> 00:23:15,680
that there are some patients 
where, where you have quite a, a

391
00:23:15,680 --> 00:23:20,640
large proportion of, of, of, of 
hyperinflammatory myeloid cells 

392
00:23:20,640 --> 00:23:24,520
in, in the, in the CNS or 
whether it's a, it's a cytokine 

393
00:23:24,520 --> 00:23:28,640
mediated phenomenon that there 
are specific cytokines which do 

394
00:23:28,640 --> 00:23:32,960
go to the, to the CNS in there. 
And, and, and, and, and use the 

395
00:23:32,960 --> 00:23:34,600
mood symptoms and, and, and the 
fatigue. 

396
00:23:35,000 --> 00:23:38,880
It's it's an open question, but 
clinically it's highly relevant.

397
00:23:39,720 --> 00:23:42,120
Wow. 
I think we came really very well

398
00:23:42,120 --> 00:23:45,720
around the whole subject here. 
So, so I think thank you so much

399
00:23:45,760 --> 00:23:50,480
Dominique for enlightening all 
this complex of of inflammation 

400
00:23:50,480 --> 00:23:54,560
and MD's which I think we can 
work on many years as we still 

401
00:23:55,360 --> 00:23:58,200
and I hope that sometimes this 
will lead to to new treatments 

402
00:23:58,200 --> 00:23:59,800
for MD's patients. 
So thank you very much. 

403
00:24:00,240 --> 00:24:03,520
Thank you, Kirsten. 
It was a very nice conversation.

404
00:24:03,520 --> 00:24:03,920
Thanks.