iwMDS 2022 | Inflammation, immune dysregulation and targeting in MDS

Uwe Platzbecker:

Hello everybody. A warm welcome here at the iwMDS Meeting. I think it’s a great meeting so far. And it’s also a great pleasure to welcome three eminent researchers in the field of MDS: Daniel Starczynowski, David Sallman, and Alan List, is sitting on the left side. The topic and also the idea of this little 10-minute break here is to give you some insights, what happened, and also some opinions on the presentations, and also the data of the last couple of hours.

Uwe Platzbecker:

So to all of you, and maybe, Alan, I can start with you, this was a very interesting session on innate immunity and also potential targets. What was your basically, highlight, of the last two hours? Also with regards to therapeutic agents, what is very close to the clinic and may enter also the clinical stage very soon for our patients?

Alan List:

Sure. It’s interesting to see that, such a focus on innate immunity when 10 years ago there was nothing. And I think it’s obviously biologically very relevant to this disease. We heard a lot about inhibitors or strategies to inhibit the Myddosome, downstream of the toll-like receptors. We also heard, we talked about inflammasome and inhibitors of the inflammasome as well.

Alan List:

We also heard about NK cells as a therapeutic target and there isn’t a lot out there, but at least in that recent press release of, it was like three patients that were treated, all achieved a CR. It’s pretty impressive, using NK cell therapy that could achieve that. I think the challenge for commercial development will be, how do you put that on a commercial scale to give one and a half billion cells three times. But I think that the first agent to really get into that space of inhibiting the Myddosome was the one that you’re involved with, the Curis agent. Do you want to talk about that?

Uwe Platzbecker:

Yeah, I mean, the presentation also had part of the clinical data already, and the stage of the development is a Phase I / Phase II clinical trial with a IRAK inhibitor, which is rather selective for IRAK-4. And what we have seen so far is clinical activity with regards to reduction of blast count, even CRs have been observed in patients with a FLT3 mutation. There was some concern with regards to safety, and I touched based on that, with rhabdomyolysis. Therefore, I think the study is currently on hold, but as I understood the company is quite optimistic to continue with that.

Uwe Platzbecker:

Thank you very much for pointing out this IRAK-4 modulation as a potential therapeutic target in MDS and AML. The world expert is sitting there. I think actually the trial, Dan, was based on your pivotal work you have published a couple of years ago. And you showed us an update. So can you elude a little bit on the role of IRAK-1 on maybe compensating selective inhibition of IRAK-4?

Daniel Starczynowski:

Yeah, no. And I just want to maybe backtrack a little bit and just sort of touch a point on how the field has really evolved over the last 10 years, particularly with the role that the innate immune inflammatory pathways are playing in this disease. The genetic catalog of mutations is well described. And now it’s really interesting how these commonly recurring mutations are largely, many of them, impinging on these innate immune inflammatory pathways in a way that’s contributing to the disease pathogenesis.

Daniel Starczynowski:

So the study you’re referring to from a few years ago, our team was able to provide one of the initial links between a common somatic mutation, a splicing factor, to activation of these innate immune signaling pathways, and specifically generation of an IRAK-4 isoform that’s just more activated. This is a druggable enzyme. And so, as you mentioned, Curis’ IRAK-4 inhibitor has moved into low-risk and high-risk and AML trials with the goal to evaluate the role of an IRAK-4 inhibitor in these patients.

Daniel Starczynowski:

What I appreciate today from this session is understanding how little I understand still about some of these pathways and how complex they are. There is a lot of crosstalk. There are complex circuits that are dysregulated in MDS and AML and the crosstalk between the inflammasome also, within the innate immune system and the Myddosome but also within the signaling pathways. And understanding compensation pathways that if targeted in a very deliberate specific way can improve the efficacy of some of these agents. So I still view this as the early days of targeting the innate immune inflammasome pathways in these diseases, but with each of these lab-based experiments and papers, as well as the clinical trials, we’re learning more about the pathways and where we need to place the greatest emphasis.

Uwe Platzbecker:

Thank you. So David, in the New England Journal a couple of weeks ago, there was, I would say, a seminal paper on patients with colorectal cancer, MSI positive, receiving no operation, no radiotherapy, just treated with checkpoint inhibitors for mild malignancies. Is the future bright with regards to, let’s say, immune based therapies? Will this be the single, maybe therapeutic approach? Can we abandon HMAs, venetoclax, everything? Is this your take-home message from the data presented or should we be a little bit more cautious?

David Sallman:

Yeah, I mean, I think that would be a pipe dream for us to have, right? I mean, having truly disease modifying therapies, therapies that we may ultimately need, let’s say allogeneic stem cell transplant, is definitely a hope that all of us have. I think that trial is a very specific setting, where fortunately these patients are having truly remarkable outcomes. I think to Dan, Alan’s point, it’s a very complex disease. Not just with different pathways being impacted, different mutations, different clinical risk scores.

David Sallman:

And the challenges a little bit are paradigm for drug development. We test one agent in one setting with one endpoint and we get some sort of lukewarm sort of data that we don’t necessarily know what to deal with. So I think we really have to come together with novel endpoints, novel combinations really early on and ideally trying to get insight into the biomarkers for this disease, whether or not it’s inhibition of the Myddosome, inflammasome, whether or not not it’s colonal eradication. Other things that really truly give us insight to where we can really hope that maybe we can have that home run to where maybe we don’t need cytotoxic chemotherapy, therapies that have lots of other challenges.

David Sallman:

So I think the future is there. I think realistically we are in the 10 to 20 years to get there, but maybe we will find subsets of patients based on great translational work. But I think we have to think a little bit more out of the box than what we are to really move the field forward more quickly.

Uwe Platzbecker:

So maybe I think we are now at eight minutes and we should have a conversation for 10. So maybe briefly, just in a vision to all of you, how do we treat, let’s say, low-risk MDS and high-risk MDS/AML in 10 years? What is your suggestion?

Alan List:

Ah, so I think the most exciting thing I would love to see is be able to target the pathobiology that’s driving the disease. And I think there’s an array of inflammasome inhibitors that are being developed right now, which are very exciting. There’s two general classes. One is what they call the ATPase inhibitors. The other one inhibits protein-protein interactions.

Alan List:

But I think that the things that’ll be important for that to be a success is not just to be able to block the activation of the NLRP3 inflammasome, but how do we deal with the complexes that are already activated, and remain catalytically active and circulate for long periods of time? I think all those things will have to be taken into account, but I would love to see that be the new therapy in the future for low-risk MDS and maybe even CCUS as well.

Uwe Platzbecker:

Then will we maybe change treatments in between when new mutations or maybe a new immunologic pattern is evolving? Is this something like a metronomic therapy? Could you envision that? Of course, it’s a little hypothetical question, but…

David Sallman:

Sure. No, I think it’s a great question. Maybe I’ll give a little bit of insight into what I feel the high-risk paradigm will be. I think fortunately now we have three drugs, in appropriately run studies. Two of which target the immune system that we discussed today, magrolimab targeting CD47, sabatolimab targeting TIM-3, and hopefully these are going to make the initial bar moving forward. Although where do I see us in 5 to 10 years? I really think we are going to move towards triplet, maybe quadruplet, studies. We have to balance toxicity at the same time, but hopefully we can really get great knowledge on translational work in the setting of these studies to maybe answer kind of some of the questions that you just have.

David Sallman:

So I really hope that in the near future, we have a much higher percentage of patients in high quality remissions and really the MRD, which has really changed the landscape of hematologic malignancies is truly going to have major significance in MDS. I think we’ve not had those therapies, but as those therapies are coming, hopefully we can read out at one month, at three months, “Hey, this combination is looking better.” And then we can really pivot into sort of more definitive trials at that time.

Uwe Platzbecker:

And Dan?

Daniel Starczynowski:

Yeah, I’ll be very brief. And again, I don’t treat patients, so that’s a full disclosure, but I think IRAK inhibitors, this is the prime time now to evaluate them in the clinic. We’ll understand a lot more about their monotherapy activity. But I think moving forward the right combinations are going to be very likely and those have to be driven by great science and justified by basic science. And then down the road, I think as we understand the complex nature of the different mutations and how they’re activating and impinging and dysregulating, not only these innate immune inflammatory pathways in the disease propagating cells, but also in the immune effector cells, and understanding that science and using that science as a foundation then to deliberately target them in a very genetically specific way. And that’s going to be more likely the longer term strategy.

Uwe Platzbecker:

So I think you’ve got a little bit of the fire and, let’s say, of the concept also of this meeting, which was to give short presentations. Some of us did, some of us did not, and also to foster the discussion. And also I think the atmosphere is very vivid. We hope that we could deliver this also here in this format.