Latest / EHA Unplugged / Targeting the Immune System in MDS (featuring Prof Dominik Wolf)

Transcript

Targeting the Immune System in MDS (featuring Prof Dominik Wolf) · EHA Unplugged

• 0:07
  Greetings and welcome to EHA Unplugged, the official podcast
• 0:11
  channel of the European Hematology Association EHA.
• 0:15
  So today I would like to welcome Dominic Wolf.
• 0:18
  He is from the Medical University of Innsbruck in
• 0:22
  Austria, and he's an expert in the immune system in MD's.
• 0:28
  So we're going to talk a little bit about targeting the immune
• 0:31
  system in MD's. So welcome, Dominique, It's nice
• 0:35
  that you could join us. I mean, we all know that
• 0:40
  transplantation works in MD's, right?
• 0:42
  And in essence, this is actually using the immune system to
• 0:47
  targeting MD's. So.
• 0:49
  So why do you think it works? I think so.
• 0:53
  First of all, thank you for the invitation.
• 0:55
  Great to be here. And yeah, allotransplantation is
• 1:00
  the prototype of immunotherapy for hematological diseases,
• 1:06
  which we all use for since decades.
• 1:10
  And then we all like it on one hand, but also we all dislike it
• 1:14
  on the other hand, because it's, it's, it's saved life.
• 1:17
  It saves a lot of lives also for particularly high risk MD's
• 1:21
  patients, but also it, it harms patients due to its toxicities
• 1:26
  in terms of non relapse related toxicities, which is one of the
• 1:31
  major limitations. And there's a lot of
• 1:33
  advancement, but it's still a big problem in in daily clinical
• 1:36
  practice, particularly in GVHD management and all that stuff.
• 1:39
  I'm personally quite convinced due to the long experia I have
• 1:43
  myself in transplantation of MD's patients and also AMI
• 1:46
  patients that it's indeed that the long term success of the of
• 1:52
  the technology indeed very much depends on the graft versus
• 1:55
  disease effect. Because you can, you can really
• 1:59
  nicely see also with the new methods of of sensing relapses
• 2:04
  by by molecular markers in patients after transplantation.
• 2:08
  When you then withdraw, for example, or reduce
• 2:10
  immunosuppression or you even give donor lymphocytes as, as
• 2:13
  you know, weapons fostering the graftus leukemia effect, you can
• 2:18
  really often see that you can again go back to MRD negativity
• 2:21
  and reduce long term control of the disease.
• 2:24
  So in addition to just being a replacement therapy, the
• 2:27
  lymphocytic compartment, but also the NK compartment in the
• 2:31
  graft is definitely centrally involved in controlling the
• 2:35
  disease. But as I said, it's also the
• 2:37
  major limitation called those cells can also do do harm the,
• 2:43
  the, the recipients by inducing severe life threatening or
• 2:49
  inducing a lot of morbidity burden in patients with, with
• 2:55
  acute and, and in particularly chronic GVHD.
• 2:59
  And it's interesting the also there, there's a lot of large
• 3:02
  big data, big file analysis from EBMT showing that you have a
• 3:06
  nice correlation of, you know, chronic GVHD and Disease
• 3:10
  Control. So you can't definitely spread
• 3:13
  those two, you know, the one which is the therapeutic effect,
• 3:17
  meaning graft versus leukemia and the one which is the, let's
• 3:19
  say, side effect, the graft versus host disease.
• 3:22
  It's it's, it's somehow also linked.
• 3:26
  And I think it's still very important.
• 3:28
  We need this kind of therapy. I just came back from my round
• 3:31
  here. We have a young lady, same age,
• 3:34
  young like, you know, young, same age.
• 3:37
  I have not very young middle-aged, but you know,
• 3:40
  having high risk MD's and it's, it's, it's clear we have to go
• 3:43
  for donor search and then go for, for transplantation finally
• 3:46
  to, to cure the disease. Because not still we don't have
• 3:50
  alternatives by using the immune immune system, for example cat T
• 3:57
  cells or other immunotherapies being being a curative
• 4:01
  alternative for this patient population.
• 4:04
  But I also think you know this, this brings me to a little bit,
• 4:06
  I mean back to to earlier stages of MD's where we know a lot of
• 4:11
  things are happening in the immune system.
• 4:13
  Why do you think, what do you think would be good targets or
• 4:16
  what have you have shown to be good targets and why they're not
• 4:18
  good enough? Can you comment a little bit on
• 4:20
  that? Yeah, For me, the, the lower
• 4:22
  risk MD's patients are a beautiful prototype of how
• 4:27
  myeloid, the myeloid compartment induces inflammatory circuits,
• 4:31
  which is very important for the microenvironment in the bone
• 4:35
  marrow, meaning the also the differentiation capacity of
• 4:38
  cells and, and, but, but which can also induce in in patients.
• 4:44
  You know, all of, of, of you, you, you, you take care of, of
• 4:47
  MD's patients and you know, these patients which have
• 4:50
  inflammatory symptoms in addition to their MD's and some
• 4:55
  patients do not have any signs of, of inflammatory side effects
• 4:59
  and, and others can have really severe hyperinflammatory
• 5:02
  syndromes. I'm not talking about VEXAS,
• 5:04
  which is a very specific subtype of, of a very defined mutation.
• 5:08
  I'm talking about really the classical MD's having the, the
• 5:12
  morphological MD's having also the mutational pattern and you
• 5:16
  know, these patients having inflammatory symptoms.
• 5:18
  And I think here we we are currently learning more and more
• 5:23
  how genetics in the minded compartment compartment imprint
• 5:27
  in eight immune signaling, which finally leads to
• 5:31
  hyperinflammation to production of for example, Illinois one and
• 5:35
  Illinois 18 HMGB 1 as a, you know, final readout of
• 5:41
  activation of in of the Nile 3 inflammasome.
• 5:44
  Or we can also see activation of intracellular protein complexes
• 5:51
  which are lowering the threshold of the TLR activation signals.
• 5:56
  And there are many TLRS out out there which are usually
• 5:59
  recognizing danger signals such As for example, APS from gram
• 6:04
  negative negative bugs. And if you have mutations which
• 6:08
  affect these intracellular adapter complexes, which make
• 6:12
  signaling more likely in, in, in when the cells are exposed, for
• 6:18
  example, to to TLR activating sickness by LP's or there can
• 6:22
  also be other poor inflammatory stimuli which activate the
• 6:24
  cells. You finally get
• 6:25
  hyperinflammation, which is where you can then see in
• 6:29
  patients, neutrophilic dermatosis, fever requiring
• 6:33
  steroids, arthritis and all this stuff which we, which we, we can
• 6:37
  see in clinics. And there are many studies out
• 6:40
  there trying to, you know, from understanding the basic biology
• 6:44
  of what's going on in the cells, trying to transfer this to, to
• 6:49
  clinical concepts. One concept is trying in low
• 6:53
  risk MD's to inhibit the knife three I 1 axis by Kanakinomap,
• 6:56
  for example. Also there are, you know, I have
• 7:00
  been for for seven years at at Bonn University and there's one
• 7:03
  of the leading knife 3 researchers.
• 7:05
  I kill lots and we are collaborating a lot and IK has
• 7:10
  developed for example knife 3 inhibitors developed in a spin
• 7:14
  off now taking over by by a large pharma company.
• 7:17
  So. This is not in clinical trials
• 7:19
  yet or. It's it's, it's just going into
• 7:23
  into phase one, but just showing you that knife 3 inhibit
• 7:26
  inhibition is in addition, you know, is more upstream to, to to
• 7:30
  to inhibiting I-1. So this this could be for the
• 7:33
  future. And these are the concepts
• 7:35
  trying to interfere with the knife 3 I-1 caspase one I one
• 7:40
  access. Also when you inhibit when you
• 7:43
  inhibit night 3, you could be more if efficient or this could
• 7:48
  could be a more efficient approach to to inhibit induction
• 7:51
  of pyroptosis which very much correlates to the
• 7:54
  differentiation defects and low risk MD's and which is mainly
• 7:58
  mediated by night 3 induced activation of caspase 1.
• 8:03
  And how do you see, because I think you know with there's the
• 8:06
  inflammation in the microenvironment and then
• 8:07
  there's the inflammation in the myeloid cells in the clone.
• 8:11
  So, so how do you see this interaction?
• 8:12
  Is the one dependent on the other or are you inhibiting both
• 8:16
  the microenvironment and the clone or?
• 8:19
  I think we need to target both. It's a very good point you
• 8:22
  mentioned because it's always like a chimera in the bone
• 8:24
  marrow. You have the diseased clonal
• 8:26
  cells and you have the non diseased cells.
• 8:28
  And I think we can learn a lot from from the story of MPNS
• 8:32
  because at the beginning we thought, okay, it's the Jack 2
• 8:34
  mutant cells where we have to inhibit Jack 2.
• 8:39
  And finally, particularly on a basis on a beautiful work from
• 8:42
  Ross Levine, we have learned that inhibition of Jack two in
• 8:45
  the non clonal compartment is very much involved in also
• 8:49
  affecting the clonal expansion. So it's, you know, those cells
• 8:52
  always interact. There's the clonal cell which
• 8:54
  has a genetic event which produces cytokine and the other
• 8:57
  one responds to this thing also to the to the the the danger
• 9:01
  patterns in the microenvironment in the bone marrow and they all
• 9:05
  it's it's like a full year dirt. So it's it's the non cloning
• 9:08
  cloning compartment. Probably we have to target them
• 9:10
  both of them, but we are not there that we understand the
• 9:13
  mechanisms in that detail. And I think also based on the on
• 9:16
  the development of single cell technologies, for example, we
• 9:19
  are currently establishing a technology, we are doing a lot
• 9:23
  of single cell sequencing work and we, we, we develop a so
• 9:27
  transcriptomic sequencing, but we, we need to annotate when you
• 9:30
  have, when we have a single transcriptome, the whole
• 9:33
  transcriptome of a single cell, I need to know the genetic
• 9:36
  background of this cell. And particularly in the
• 9:38
  hematology where you have different clones having one
• 9:41
  mutation 1 plus the other mutation and cells which are non
• 9:44
  mutated normal hematocritic cells, we need to understand so
• 9:47
  which pathways are really induced there to really more or
• 9:52
  deliver develop more more targeted approaches on the basis
• 9:57
  of anti-inflammatory treatment. But I think my three I one is 1
• 10:01
  possibility which is very interesting in in low risk and
• 10:05
  years where the differentiation problem, the cytopenia is the
• 10:08
  main problem. Yeah.
• 10:10
  Another, another development is, is, is, is is targeting the the
• 10:14
  Mighty 88 complex where Iracs are essential in, in, in the
• 10:18
  signalling complex. And that's the one we know from
• 10:21
  the lymphoid diseases, right? Yes, exactly.
• 10:23
  That's the one we know from from lymphoma and from widen sperm
• 10:27
  disease. It's it's mighty 888 mutations.
• 10:31
  But here we have different kind. It's not the classical Mighty 88
• 10:35
  mutated activation of the Mighty 88 complex.
• 10:38
  It's rather based on proteins which are part of the complex
• 10:42
  and Iracs play an essential role in the normal Mighty 88 induced
• 10:47
  ELR signalling transduction into the cell leading to the output
• 10:51
  of producing cytokines. For example, you know normal
• 10:54
  cell response to APS in in a sepsis and bacteria exposure.
• 11:00
  And here we have based on spliceosome mutations, IRAC can
• 11:04
  be differentially spliced and then we have an overabundance of
• 11:08
  the long form of Iraq four. And this, this long form of Iraq
• 11:14
  4 leads to, to a hyperactivation of this complex and this Iraq
• 11:20
  inhibitors are clinically tested.
• 11:22
  There is some data out there. It, it seems promising, but it's
• 11:27
  very early. And you know, the basic idea is
• 11:30
  also to, to trying to, to interfere with this inflammatory
• 11:36
  signalling circuit in, in, in, in MD's.
• 11:41
  And do you think this is even part of the whole I mean the the
• 11:46
  the way that this arises, you know, when you go from from
• 11:50
  cheap or sequence to MDSI mean this is is this driven by
• 11:53
  inflammation, you think, or is it is it the what do you?
• 11:57
  And is it mutation to different types of mutation also or how
• 12:01
  do? You, it's a very good question.
• 12:03
  I mean, I think it's, I think I mean everybody or it's, it's,
• 12:09
  let's say it's, it's, it's accepted that chronic
• 12:12
  inflammation leads to loss production and chronic local
• 12:19
  stress of hematopoietic cells. And I could envision that
• 12:22
  chronic inflammation also induces the cloner development
• 12:32
  or clonal development or clonal expansion of, of, of, of chip
• 12:36
  clones, then leading by somehow having hyper proliferative
• 12:40
  features leading to secondary genetic events, really finally
• 12:44
  ending up in a, in a dysplasia coming from, you know, normal
• 12:47
  hematopoietic output from clonal hematopoiesis, perhaps going
• 12:52
  over C cast and really going to dysplasia, which may be at least
• 12:56
  in some patients very much depend on on induction of
• 13:00
  pyoptosis by activation of the I-1 pathway.
• 13:03
  But I'm, I'm not so sure whether, because Chip is so
• 13:07
  frequent and, and I'm not so sure whether this is the only,
• 13:13
  whether the, the inflammation in the Chip clone itself is the
• 13:17
  only driving force. I think it very it could be that
• 13:20
  that there are other inflammatory external micro
• 13:24
  environmental driven forces. And I think there's a beautiful
• 13:29
  model coming from lung cancer where, you know, Charlie Swanton
• 13:33
  has just recently published this air pollutant paper where they
• 13:37
  show that in in the lung we have, you know, let's say the
• 13:40
  lung chip is the GFR mutation in the epithelial cells.
• 13:44
  But then then you have the microparticle dust exposure
• 13:48
  which induces like green flamosome in myeloid cells,
• 13:51
  particularly macrophages. And this inflammatory stress by
• 13:55
  the air pollutants induces then the transformation and then the
• 13:58
  CARAS mutation comes on top and then you see the transformation.
• 14:02
  And they have really shown beautifully that EGFR mutated
• 14:06
  lung cancer is, is directly correlating to the, to the
• 14:11
  microparticle exposure. When you look at, you know, the
• 14:13
  big cities in, in, in Asia that the, the, the, and you compare
• 14:18
  this to probably, let's say one of our side values here.
• 14:22
  It's, it's, it's really a highly, a highly correlated
• 14:27
  observation. And I think we could, it could
• 14:29
  be that we have the same model here.
• 14:31
  We have a spontaneous age-related sensitivity of
• 14:36
  hematopoietic cells to to get a chip lesion.
• 14:39
  And then we have external factors.
• 14:41
  There was a recent paper showing that for example, Adipositus is
• 14:44
  driving clonal expansion of chip clones in a, in a, in a nice
• 14:48
  mirror and model. So this, I think it's a it's a
• 14:52
  very complex mixture, but it's for me, it's hot topic because
• 14:55
  it. So do you think we can prevent
• 14:58
  MD's progression? Yeah, Perhaps we can prevent and
• 15:01
  progression by by being efficiently, more efficiently
• 15:06
  having anti clonal therapies. I think we have to reduce the
• 15:10
  clonal size and we have to reduce inflammation,
• 15:12
  anti-inflammatory and anti clonal.
• 15:15
  And it's a bit like when you go to MPN, it's a different field.
• 15:19
  But conceptually you can induce anti clonal therapy with
• 15:22
  interferon. It's an and you can be very
• 15:28
  perfectly anti-inflammatory with drug inhibitors, but you don't
• 15:32
  have this very, very strong anti clonal drugs in, in, in, in, in,
• 15:36
  in low risk MD's because we can't, you know, interferon is
• 15:39
  not, is not a good idea in this setting.
• 15:41
  But conceptually I think it it it that would be interesting.
• 15:45
  So, so, so is this because we actually don't have anything
• 15:49
  that reduces the clone and lower risk?
• 15:51
  And yes. Yes, we, we, we could perhaps
• 15:53
  reduce the clone by, by, by ADSAP, but but we don't use it
• 15:58
  in this sense. We would rather try to to
• 16:00
  reinforce blood production by by growth factors or lose, Batter
• 16:05
  said. Which is also some kind of, you
• 16:07
  know. There was an interesting talk by
• 16:09
  Valier Santini on at the SA showing that Emitlestat could
• 16:13
  actually reduce the clones, but I don't that was that was sort
• 16:17
  of for me a completely new discovery I think.
• 16:21
  Definitely. What about the, what about the
• 16:24
  adaptive immune system does that?
• 16:26
  I mean people have been trying to target that in MD's.
• 16:28
  What do you think about that? Very difficult data are not
• 16:31
  convincing. We don't have the right targets.
• 16:34
  We don't understand the targets when when it comes, for example,
• 16:37
  to checkpoint inhibitors, there are many, many trials, but the
• 16:40
  data is disappointing. The only check inhibitors which
• 16:43
  which which which seems to be interesting.
• 16:46
  I mean, Neil Davis has published in the May issue of of JC or for
• 16:49
  example, the combination of macro Mac olimab together with
• 16:52
  other cited in, in, in in high risk, higher risk MD's patients.
• 16:56
  So I think these the, the, the, the myeloid checkpoints seem to
• 16:59
  be more interesting. The team three data are a bit
• 17:02
  disappointing. The stimulus first stimulus
• 17:04
  Phase 2 is a bit disappointing. But let's see what's what's
• 17:07
  coming out there in the, in the randomized phase three.
• 17:09
  I think we have to dig deeper and probably it's also due to
• 17:13
  the complexity of the of the disease, the all Comer studies
• 17:17
  with these kind of approaches very likely not to be positive.
• 17:22
  So I think we need to understand the basic biology better to more
• 17:26
  to better preselect patients, which are probably the ones
• 17:28
  which select, for example, from Macoli MAP or from Tim 3
• 17:32
  antibodies. Or perhaps there are even some
• 17:34
  of them which may be sensitive to, to, to, to classical
• 17:40
  checkpoint inhibitors such as EPILIMO MAP or NIBO.
• 17:43
  But actually in the in, in, in the study so far, the signals
• 17:46
  are not very strong. The signals for macolimab are
• 17:48
  strong. I mean, the C, the CR rate is
• 17:51
  something between 3540%. The overall response rate is
• 17:55
  good. The TP 53 mutants seem to be
• 17:58
  very encouraging. And even if you and if you then
• 18:00
  go to transplant, the data looks quite interesting.
• 18:04
  So I think it's early, but it's a very good and interesting
• 18:07
  approach. Yeah.
• 18:08
  And probably that's probably one of the very few things we've
• 18:11
  seen working in TP53 Muted definitely.
• 18:14
  And of course also if we go more to the experimental side, what
• 18:17
  about cut teas in in MD's AML? Do you think that will have, I
• 18:22
  think that will have a role or? Yeah.
• 18:24
  One problem is the target, yeah, it's a hematopoietic derived
• 18:30
  hematopoietic stem cell derived disease.
• 18:31
  So the the targets are often shared with normal hematopoietic
• 18:34
  stem cells. I mean, we all know the the
• 18:36
  paper from 218 published in cell in, in, in, in, in monkeys and
• 18:42
  in preclinical models that that you can combine stem cell
• 18:46
  transplantation, taking out the the 33 by by and transplant the
• 18:53
  stem cells without the target together with the T cells
• 18:56
  targeting the target on the myeloid cells.
• 18:58
  But I think it's a very complex setting and the appropriate
• 19:06
  targets are currently really lacking.
• 19:09
  There are early clinical trials of, of technologies trying not
• 19:14
  to use CAR T cells which already have the, the, the single chain
• 19:19
  bound to the transplant domain. So that you, if you, if you
• 19:22
  infuse the CAR T cell that it goes directly to, to, to the
• 19:26
  targets on the Myelo cells, but also on the, on the healthy
• 19:29
  cells, but then use adapters. So you have a CAR T cell which
• 19:33
  is somehow cold and you have, for example, a leucine SIPA.
• 19:38
  And then you give a we have a drug which on one hand side
• 19:41
  targets the myeloid target and on the other hand side you can
• 19:45
  you it, it binds to the to the cold CAR T cell.
• 19:47
  But you can compete with these small drugs when they induce
• 19:51
  toxicity such as CVS CIS, but also perhaps inducing a
• 19:56
  pleasure. But I think addressing and and
• 20:00
  identification of of the of the most appropriate targets is is
• 20:03
  one of the. Biggest problems we, we, we have
• 20:06
  not only in, in, in myeloid diseases, also in T cell
• 20:10
  lymphomas, for example, where everybody, you know, it's so
• 20:12
  hard to treat, so difficult and, and no CAR T cell therapy
• 20:16
  available. It, it, it's, it's, it's a pity.
• 20:18
  And I think we have to to dig deeper there that, that there is
• 20:22
  early clinical trials on CAR T cells also in, in MD's patients,
• 20:25
  but it's definitely too early and it's, it's, it's far from
• 20:28
  clinic to be honest. And isn't it also a problem that
• 20:32
  sort of MDI mean if you have an advanced MD's, almost all the
• 20:36
  stem cells are part of the clone, right?
• 20:38
  So, so will there be residual stem cells if we attack them?
• 20:41
  We say it once, I don't know, you know, it's isn't that an
• 20:45
  issue also that we almost need to have a transplantation on top
• 20:49
  or. Yeah.
• 20:51
  And then you can ask, I mean, what is, what is then the net
• 20:54
  benefit of of doing it when you anyhow have to go for for for a
• 20:57
  chance? And it's probably.
• 21:00
  Too healthy you don't have the possibility to have an
• 21:02
  ontologist re grafting because you don't have healthy stem
• 21:05
  cells. I think that for me in myeloid
• 21:08
  diseases, alotransplantation will be in place for the next,
• 21:14
  let's say at least for a decade. Yeah.
• 21:17
  I don't see the developments which can replace Aloe for high
• 21:21
  risk MD's so far currently. You know, I more see the
• 21:25
  anti-inflammatory potential in earlier lines of MD's and the
• 21:28
  hyperinflammatory patients. But you know, in in high risk
• 21:32
  MD's patients, I, I, I, I see transplantation in place for the
• 21:35
  next at least. So in the early phase is
• 21:38
  actually more preventing progression and yeah,
• 21:41
  definitely. Yeah.
• 21:42
  And there we have to understand, I mean we just recently finished
• 21:45
  a project where we collected 100 patients and we want to
• 21:49
  understand because we know in lower risk MD's fatigue is a
• 21:52
  strong. Yeah.
• 21:54
  Strong driver of is is a prognostic factor and and why is
• 21:59
  that the case? What, what is fatigue really?
• 22:01
  I mean, also in long COVID, what is the fatigue?
• 22:04
  I mean, is it is it subtle chronic inflammation?
• 22:07
  And I think in in MD's we should really trying to dissect and
• 22:11
  bring together fatigue, which is not a result of having a low
• 22:15
  hemoglobin, it's a result of hyperinflammation probably.
• 22:18
  And we have to understand which mutations to induce which
• 22:21
  pattern of cytokines which then induces fatigue, which may also
• 22:25
  drive the the the the the the more quick transformation to
• 22:29
  over the AML then or which which then is a is a potentially life
• 22:33
  threatening situation. I think that's a very
• 22:36
  interesting end point because this is also one that really
• 22:38
  means a lot for the patients, right?
• 22:40
  So, so do you think this inflammation is actually in the
• 22:43
  central nervous system or, or how do you envision the
• 22:46
  combination of inflammation and fatigue?
• 22:49
  It could, it could be that it's, it's a very good point that it's
• 22:52
  a, it's an inflammation which also effects the, the CNS and,
• 22:57
  and thereby induces the mood symptoms.
• 23:00
  But, but the problem is that we do not know.
• 23:03
  We do nothing. We do know nothing about, you
• 23:06
  know, the, the, the clonal composition of the, for example,
• 23:08
  the myeloid cells in the brain. Whether that takes, you know
• 23:11
  that there are some patients where, where you have quite a, a
• 23:15
  large proportion of, of, of, of hyperinflammatory myeloid cells
• 23:20
  in, in the, in the CNS or whether it's a, it's a cytokine
• 23:24
  mediated phenomenon that there are specific cytokines which do
• 23:28
  go to the, to the CNS in there. And, and, and, and, and use the
• 23:32
  mood symptoms and, and, and the fatigue.
• 23:35
  It's it's an open question, but clinically it's highly relevant.
• 23:39
  Wow. I think we came really very well
• 23:42
  around the whole subject here. So, so I think thank you so much
• 23:45
  Dominique for enlightening all this complex of of inflammation
• 23:50
  and MD's which I think we can work on many years as we still
• 23:55
  and I hope that sometimes this will lead to to new treatments
• 23:58
  for MD's patients. So thank you very much.
• 24:00
  Thank you, Kirsten. It was a very nice conversation.
• 24:03
  Thanks.