Greetings and welcome to EHA Unplugged, the official podcast
channel of the European Hematology Association EHA.
So today I would like to welcome Dominic Wolf.
He is from the Medical University of Innsbruck in
Austria, and he's an expert in the immune system in MD's.
So we're going to talk a little bit about targeting the immune
system in MD's. So welcome, Dominique, It's nice
that you could join us. I mean, we all know that
transplantation works in MD's, right?
And in essence, this is actually using the immune system to
targeting MD's. So.
So why do you think it works? I think so.
First of all, thank you for the invitation.
Great to be here. And yeah, allotransplantation is
the prototype of immunotherapy for hematological diseases,
which we all use for since decades.
And then we all like it on one hand, but also we all dislike it
on the other hand, because it's, it's, it's saved life.
It saves a lot of lives also for particularly high risk MD's
patients, but also it, it harms patients due to its toxicities
in terms of non relapse related toxicities, which is one of the
major limitations. And there's a lot of
advancement, but it's still a big problem in in daily clinical
practice, particularly in GVHD management and all that stuff.
I'm personally quite convinced due to the long experia I have
myself in transplantation of MD's patients and also AMI
patients that it's indeed that the long term success of the of
the technology indeed very much depends on the graft versus
disease effect. Because you can, you can really
nicely see also with the new methods of of sensing relapses
by by molecular markers in patients after transplantation.
When you then withdraw, for example, or reduce
immunosuppression or you even give donor lymphocytes as, as
you know, weapons fostering the graftus leukemia effect, you can
really often see that you can again go back to MRD negativity
and reduce long term control of the disease.
So in addition to just being a replacement therapy, the
lymphocytic compartment, but also the NK compartment in the
graft is definitely centrally involved in controlling the
disease. But as I said, it's also the
major limitation called those cells can also do do harm the,
the, the recipients by inducing severe life threatening or
inducing a lot of morbidity burden in patients with, with
acute and, and in particularly chronic GVHD.
And it's interesting the also there, there's a lot of large
big data, big file analysis from EBMT showing that you have a
nice correlation of, you know, chronic GVHD and Disease
Control. So you can't definitely spread
those two, you know, the one which is the therapeutic effect,
meaning graft versus leukemia and the one which is the, let's
say, side effect, the graft versus host disease.
It's it's, it's somehow also linked.
And I think it's still very important.
We need this kind of therapy. I just came back from my round
here. We have a young lady, same age,
young like, you know, young, same age.
I have not very young middle-aged, but you know,
having high risk MD's and it's, it's, it's clear we have to go
for donor search and then go for, for transplantation finally
to, to cure the disease. Because not still we don't have
alternatives by using the immune immune system, for example cat T
cells or other immunotherapies being being a curative
alternative for this patient population.
But I also think you know this, this brings me to a little bit,
I mean back to to earlier stages of MD's where we know a lot of
things are happening in the immune system.
Why do you think, what do you think would be good targets or
what have you have shown to be good targets and why they're not
good enough? Can you comment a little bit on
that? Yeah, For me, the, the lower
risk MD's patients are a beautiful prototype of how
myeloid, the myeloid compartment induces inflammatory circuits,
which is very important for the microenvironment in the bone
marrow, meaning the also the differentiation capacity of
cells and, and, but, but which can also induce in in patients.
You know, all of, of, of you, you, you, you take care of, of
MD's patients and you know, these patients which have
inflammatory symptoms in addition to their MD's and some
patients do not have any signs of, of inflammatory side effects
and, and others can have really severe hyperinflammatory
syndromes. I'm not talking about VEXAS,
which is a very specific subtype of, of a very defined mutation.
I'm talking about really the classical MD's having the, the
morphological MD's having also the mutational pattern and you
know, these patients having inflammatory symptoms.
And I think here we we are currently learning more and more
how genetics in the minded compartment compartment imprint
in eight immune signaling, which finally leads to
hyperinflammation to production of for example, Illinois one and
Illinois 18 HMGB 1 as a, you know, final readout of
activation of in of the Nile 3 inflammasome.
Or we can also see activation of intracellular protein complexes
which are lowering the threshold of the TLR activation signals.
And there are many TLRS out out there which are usually
recognizing danger signals such As for example, APS from gram
negative negative bugs. And if you have mutations which
affect these intracellular adapter complexes, which make
signaling more likely in, in, in when the cells are exposed, for
example, to to TLR activating sickness by LP's or there can
also be other poor inflammatory stimuli which activate the
cells. You finally get
hyperinflammation, which is where you can then see in
patients, neutrophilic dermatosis, fever requiring
steroids, arthritis and all this stuff which we, which we, we can
see in clinics. And there are many studies out
there trying to, you know, from understanding the basic biology
of what's going on in the cells, trying to transfer this to, to
clinical concepts. One concept is trying in low
risk MD's to inhibit the knife three I 1 axis by Kanakinomap,
for example. Also there are, you know, I have
been for for seven years at at Bonn University and there's one
of the leading knife 3 researchers.
I kill lots and we are collaborating a lot and IK has
developed for example knife 3 inhibitors developed in a spin
off now taking over by by a large pharma company.
So. This is not in clinical trials
yet or. It's it's, it's just going into
into phase one, but just showing you that knife 3 inhibit
inhibition is in addition, you know, is more upstream to, to to
to inhibiting I-1. So this this could be for the
future. And these are the concepts
trying to interfere with the knife 3 I-1 caspase one I one
access. Also when you inhibit when you
inhibit night 3, you could be more if efficient or this could
could be a more efficient approach to to inhibit induction
of pyroptosis which very much correlates to the
differentiation defects and low risk MD's and which is mainly
mediated by night 3 induced activation of caspase 1.
And how do you see, because I think you know with there's the
inflammation in the microenvironment and then
there's the inflammation in the myeloid cells in the clone.
So, so how do you see this interaction?
Is the one dependent on the other or are you inhibiting both
the microenvironment and the clone or?
I think we need to target both. It's a very good point you
mentioned because it's always like a chimera in the bone
marrow. You have the diseased clonal
cells and you have the non diseased cells.
And I think we can learn a lot from from the story of MPNS
because at the beginning we thought, okay, it's the Jack 2
mutant cells where we have to inhibit Jack 2.
And finally, particularly on a basis on a beautiful work from
Ross Levine, we have learned that inhibition of Jack two in
the non clonal compartment is very much involved in also
affecting the clonal expansion. So it's, you know, those cells
always interact. There's the clonal cell which
has a genetic event which produces cytokine and the other
one responds to this thing also to the to the the the danger
patterns in the microenvironment in the bone marrow and they all
it's it's like a full year dirt. So it's it's the non cloning
cloning compartment. Probably we have to target them
both of them, but we are not there that we understand the
mechanisms in that detail. And I think also based on the on
the development of single cell technologies, for example, we
are currently establishing a technology, we are doing a lot
of single cell sequencing work and we, we, we develop a so
transcriptomic sequencing, but we, we need to annotate when you
have, when we have a single transcriptome, the whole
transcriptome of a single cell, I need to know the genetic
background of this cell. And particularly in the
hematology where you have different clones having one
mutation 1 plus the other mutation and cells which are non
mutated normal hematocritic cells, we need to understand so
which pathways are really induced there to really more or
deliver develop more more targeted approaches on the basis
of anti-inflammatory treatment. But I think my three I one is 1
possibility which is very interesting in in low risk and
years where the differentiation problem, the cytopenia is the
main problem. Yeah.
Another, another development is, is, is, is is targeting the the
Mighty 88 complex where Iracs are essential in, in, in the
signalling complex. And that's the one we know from
the lymphoid diseases, right? Yes, exactly.
That's the one we know from from lymphoma and from widen sperm
disease. It's it's mighty 888 mutations.
But here we have different kind. It's not the classical Mighty 88
mutated activation of the Mighty 88 complex.
It's rather based on proteins which are part of the complex
and Iracs play an essential role in the normal Mighty 88 induced
ELR signalling transduction into the cell leading to the output
of producing cytokines. For example, you know normal
cell response to APS in in a sepsis and bacteria exposure.
And here we have based on spliceosome mutations, IRAC can
be differentially spliced and then we have an overabundance of
the long form of Iraq four. And this, this long form of Iraq
4 leads to, to a hyperactivation of this complex and this Iraq
inhibitors are clinically tested.
There is some data out there. It, it seems promising, but it's
very early. And you know, the basic idea is
also to, to trying to, to interfere with this inflammatory
signalling circuit in, in, in, in MD's.
And do you think this is even part of the whole I mean the the
the way that this arises, you know, when you go from from
cheap or sequence to MDSI mean this is is this driven by
inflammation, you think, or is it is it the what do you?
And is it mutation to different types of mutation also or how
do? You, it's a very good question.
I mean, I think it's, I think I mean everybody or it's, it's,
let's say it's, it's, it's accepted that chronic
inflammation leads to loss production and chronic local
stress of hematopoietic cells. And I could envision that
chronic inflammation also induces the cloner development
or clonal development or clonal expansion of, of, of, of chip
clones, then leading by somehow having hyper proliferative
features leading to secondary genetic events, really finally
ending up in a, in a dysplasia coming from, you know, normal
hematopoietic output from clonal hematopoiesis, perhaps going
over C cast and really going to dysplasia, which may be at least
in some patients very much depend on on induction of
pyoptosis by activation of the I-1 pathway.
But I'm, I'm not so sure whether, because Chip is so
frequent and, and I'm not so sure whether this is the only,
whether the, the inflammation in the Chip clone itself is the
only driving force. I think it very it could be that
that there are other inflammatory external micro
environmental driven forces. And I think there's a beautiful
model coming from lung cancer where, you know, Charlie Swanton
has just recently published this air pollutant paper where they
show that in in the lung we have, you know, let's say the
lung chip is the GFR mutation in the epithelial cells.
But then then you have the microparticle dust exposure
which induces like green flamosome in myeloid cells,
particularly macrophages. And this inflammatory stress by
the air pollutants induces then the transformation and then the
CARAS mutation comes on top and then you see the transformation.
And they have really shown beautifully that EGFR mutated
lung cancer is, is directly correlating to the, to the
microparticle exposure. When you look at, you know, the
big cities in, in, in Asia that the, the, the, and you compare
this to probably, let's say one of our side values here.
It's, it's, it's really a highly, a highly correlated
observation. And I think we could, it could
be that we have the same model here.
We have a spontaneous age-related sensitivity of
hematopoietic cells to to get a chip lesion.
And then we have external factors.
There was a recent paper showing that for example, Adipositus is
driving clonal expansion of chip clones in a, in a, in a nice
mirror and model. So this, I think it's a it's a
very complex mixture, but it's for me, it's hot topic because
it. So do you think we can prevent
MD's progression? Yeah, Perhaps we can prevent and
progression by by being efficiently, more efficiently
having anti clonal therapies. I think we have to reduce the
clonal size and we have to reduce inflammation,
anti-inflammatory and anti clonal.
And it's a bit like when you go to MPN, it's a different field.
But conceptually you can induce anti clonal therapy with
interferon. It's an and you can be very
perfectly anti-inflammatory with drug inhibitors, but you don't
have this very, very strong anti clonal drugs in, in, in, in, in,
in low risk MD's because we can't, you know, interferon is
not, is not a good idea in this setting.
But conceptually I think it it it that would be interesting.
So, so, so is this because we actually don't have anything
that reduces the clone and lower risk?
And yes. Yes, we, we, we could perhaps
reduce the clone by, by, by ADSAP, but but we don't use it
in this sense. We would rather try to to
reinforce blood production by by growth factors or lose, Batter
said. Which is also some kind of, you
know. There was an interesting talk by
Valier Santini on at the SA showing that Emitlestat could
actually reduce the clones, but I don't that was that was sort
of for me a completely new discovery I think.
Definitely. What about the, what about the
adaptive immune system does that?
I mean people have been trying to target that in MD's.
What do you think about that? Very difficult data are not
convincing. We don't have the right targets.
We don't understand the targets when when it comes, for example,
to checkpoint inhibitors, there are many, many trials, but the
data is disappointing. The only check inhibitors which
which which which seems to be interesting.
I mean, Neil Davis has published in the May issue of of JC or for
example, the combination of macro Mac olimab together with
other cited in, in, in in high risk, higher risk MD's patients.
So I think these the, the, the, the myeloid checkpoints seem to
be more interesting. The team three data are a bit
disappointing. The stimulus first stimulus
Phase 2 is a bit disappointing. But let's see what's what's
coming out there in the, in the randomized phase three.
I think we have to dig deeper and probably it's also due to
the complexity of the of the disease, the all Comer studies
with these kind of approaches very likely not to be positive.
So I think we need to understand the basic biology better to more
to better preselect patients, which are probably the ones
which select, for example, from Macoli MAP or from Tim 3
antibodies. Or perhaps there are even some
of them which may be sensitive to, to, to, to classical
checkpoint inhibitors such as EPILIMO MAP or NIBO.
But actually in the in, in, in the study so far, the signals
are not very strong. The signals for macolimab are
strong. I mean, the C, the CR rate is
something between 3540%. The overall response rate is
good. The TP 53 mutants seem to be
very encouraging. And even if you and if you then
go to transplant, the data looks quite interesting.
So I think it's early, but it's a very good and interesting
approach. Yeah.
And probably that's probably one of the very few things we've
seen working in TP53 Muted definitely.
And of course also if we go more to the experimental side, what
about cut teas in in MD's AML? Do you think that will have, I
think that will have a role or? Yeah.
One problem is the target, yeah, it's a hematopoietic derived
hematopoietic stem cell derived disease.
So the the targets are often shared with normal hematopoietic
stem cells. I mean, we all know the the
paper from 218 published in cell in, in, in, in, in monkeys and
in preclinical models that that you can combine stem cell
transplantation, taking out the the 33 by by and transplant the
stem cells without the target together with the T cells
targeting the target on the myeloid cells.
But I think it's a very complex setting and the appropriate
targets are currently really lacking.
There are early clinical trials of, of technologies trying not
to use CAR T cells which already have the, the, the single chain
bound to the transplant domain. So that you, if you, if you
infuse the CAR T cell that it goes directly to, to, to the
targets on the Myelo cells, but also on the, on the healthy
cells, but then use adapters. So you have a CAR T cell which
is somehow cold and you have, for example, a leucine SIPA.
And then you give a we have a drug which on one hand side
targets the myeloid target and on the other hand side you can
you it, it binds to the to the cold CAR T cell.
But you can compete with these small drugs when they induce
toxicity such as CVS CIS, but also perhaps inducing a
pleasure. But I think addressing and and
identification of of the of the most appropriate targets is is
one of the. Biggest problems we, we, we have
not only in, in, in myeloid diseases, also in T cell
lymphomas, for example, where everybody, you know, it's so
hard to treat, so difficult and, and no CAR T cell therapy
available. It, it, it's, it's, it's a pity.
And I think we have to to dig deeper there that, that there is
early clinical trials on CAR T cells also in, in MD's patients,
but it's definitely too early and it's, it's, it's far from
clinic to be honest. And isn't it also a problem that
sort of MDI mean if you have an advanced MD's, almost all the
stem cells are part of the clone, right?
So, so will there be residual stem cells if we attack them?
We say it once, I don't know, you know, it's isn't that an
issue also that we almost need to have a transplantation on top
or. Yeah.
And then you can ask, I mean, what is, what is then the net
benefit of of doing it when you anyhow have to go for for for a
chance? And it's probably.
Too healthy you don't have the possibility to have an
ontologist re grafting because you don't have healthy stem
cells. I think that for me in myeloid
diseases, alotransplantation will be in place for the next,
let's say at least for a decade. Yeah.
I don't see the developments which can replace Aloe for high
risk MD's so far currently. You know, I more see the
anti-inflammatory potential in earlier lines of MD's and the
hyperinflammatory patients. But you know, in in high risk
MD's patients, I, I, I, I see transplantation in place for the
next at least. So in the early phase is
actually more preventing progression and yeah,
definitely. Yeah.
And there we have to understand, I mean we just recently finished
a project where we collected 100 patients and we want to
understand because we know in lower risk MD's fatigue is a
strong. Yeah.
Strong driver of is is a prognostic factor and and why is
that the case? What, what is fatigue really?
I mean, also in long COVID, what is the fatigue?
I mean, is it is it subtle chronic inflammation?
And I think in in MD's we should really trying to dissect and
bring together fatigue, which is not a result of having a low
hemoglobin, it's a result of hyperinflammation probably.
And we have to understand which mutations to induce which
pattern of cytokines which then induces fatigue, which may also
drive the the the the the the more quick transformation to
over the AML then or which which then is a is a potentially life
threatening situation. I think that's a very
interesting end point because this is also one that really
means a lot for the patients, right?
So, so do you think this inflammation is actually in the
central nervous system or, or how do you envision the
combination of inflammation and fatigue?
It could, it could be that it's, it's a very good point that it's
a, it's an inflammation which also effects the, the CNS and,
and thereby induces the mood symptoms.
But, but the problem is that we do not know.
We do nothing. We do know nothing about, you
know, the, the, the clonal composition of the, for example,
the myeloid cells in the brain. Whether that takes, you know
that there are some patients where, where you have quite a, a
large proportion of, of, of, of hyperinflammatory myeloid cells
in, in the, in the CNS or whether it's a, it's a cytokine
mediated phenomenon that there are specific cytokines which do
go to the, to the CNS in there. And, and, and, and, and use the
mood symptoms and, and, and the fatigue.
It's it's an open question, but clinically it's highly relevant.
Wow. I think we came really very well
around the whole subject here. So, so I think thank you so much
Dominique for enlightening all this complex of of inflammation
and MD's which I think we can work on many years as we still
and I hope that sometimes this will lead to to new treatments
for MD's patients. So thank you very much.
Thank you, Kirsten. It was a very nice conversation.
Thanks.