Lawrence Boise:

Hello, I’m Lawrence Boise from the Winship Cancer Institute at Emory University. And along with my co-chair, Dr Paola Neri from the University of Calgary. We are at the Myeloma 2022 in Scottsdale, Arizona. And we just finished up with a really exciting session on novel targets in myeloma.

Lawrence Boise:

Paola, when… I love novel target sessions, because there’s a lot of variety since there’s so many different types of targets, whether they’re precision medicine approaches, like venetoclax, that I talked about, whether they’re immunotherapeutic approaches like CAR-T cells or T-cell engagers like you discussed as well. And we also heard about a new target, PIKfyve, and it’s moving potentially into the clinic in the coming year or so.

Lawrence Boise:

And so I’ve always loved to hear about that. And of course, we got to hear about some older ones too, even proteasome inhibitors and IMiDs and learning more about potential resistance mechanisms too. So what was your thought?

Paola Neri:

Yeah, even RAS, the concept of targeting RAS directly. And directly in the past, we thought was very difficult. Now we have a way to do that. So I think to your point, technology is allowing us to use different approaches to target things that we know in myeloma biology are very important. I may also comment on the fact that even studying, using more the immunotherapy for example, have allowed us to start understanding if we are predictor of response to this therapy that in the past, we didn’t think were possible. We start learning mechanisms of resistant to these approaches as well. So I think genome analyzing the tumor as well the immune cells have allowed us to understand a different level, really what matters for a patient to respond or not to an immunotherapy.

Lawrence Boise:

Yeah. And I think a great example of that was actually in the second part of your talk, when you talked about the T-cell engagers and what was involved in where you saw responses and non-response.

Paola Neri:

And that was. Yeah.

Lawrence Boise:

Can you tell us a little more about that?

Paola Neri:

That was interesting. Because I mean, we’re always wondering if we have a way to see and tell up front if the patient we’re seeing in clinic would be good candidate for immunotherapy. And I think our initial data seems to suggest that unfortunately, if we have dysfunctional T-cells present in the bone marrow, in the peripheral blood, these patients have very difficult… They don’t have much ability to respond to T-cell engagers. In contrast, the patients that have healthy, for example, memory T-cells in their peripheral blood, or even if there is an exhaustion component in the bone marrow, this could be replaced by this healthy pool of T-cells that, by being exposed to cell engagers, could just come in the bone marrow and, having an anti-tumor effect. Something very unique that I think argue about, maybe the peripheral blood will be sufficient for this patient to be profiled upfront and make the decision based on that.

Lawrence Boise:

Yeah. I know that’s going to be really important too. It’s so much more convenient for the patients themselves to have that profiling done that way. And so while we’re thinking about immunotherapy, you also talked about, with so much excitement now with our second FDA approval for our CAR-T cell. However, even with this excitement and these great responses that we’re seeing, there have been some issues with the duration of the response. And so you also talked about one potential way of armoring a CAR-T cell to maybe get over some of those issues. You want to tell us about that?

Paola Neri:

Yeah. This is actually using one of your favorite genes, the one you studied many, many years ago, the BCL-xL, BCL-2L1 that actually is a pro-survival gene, and we identified clearly was much higher in the CAR-T from sensitive patients. So we have actually armored CAR-T using this specific gene thinking that we could overcome the activation induced cell death, that we could increase the persistence, the survival of the CAR-T in patients. And actually we have done for now in vitro, in vivo studies showing that indeed these CAR-T armored are able to survive longer, to persist longer, and have longer anti-tumor effects. The next step will be talking about translating into a clinical setting, thinking that with the catch there, and I think you can comment on the two, how safest to introduce a pro-survival gene in a CAR construct. Do we need to be concerned about safety or inducing other issues? What is your thought there, Larry?

Lawrence Boise:

No, I think it’s something we will have to consider moving forward. I mean, we know that even BCL-2 itself got its name because it was an oncogene in follicular lymphoma. So introducing genes like that, there are going to be… We’ll have to just keep a real careful look at will they affect the T-cells and in a way to transform them which could potentially be harmful to the patient. But I so far in your data, it does not appear that’s going to be the case. And I think that’s really important, but we will have to monitor that moving forward.

Paola Neri:

We could also, I mean, right now we can manipulate the product to eventually add another gene, like CD20, that can be turned off and on that’s right with, for example, rituximab. So I think we are living in a time where there are a lot of strategies that we can also use to improve the product, to improve the CAR-T, to make T-cells more memory-like, less exhausted, that we know matter for their response to patients. So I think in the next few years, we’ll be very excited to see this coming up with new discoveries.

Lawrence Boise:

Yeah, absolutely. You know, inducible suicide switches for the cells. All those would be would definitely be ways that could be tested. So one of the other parts about looking, think about novel therapies, a lot of these we’re talking about are really down the road for patients, but we still have our backbone therapies, our proteasome inhibitors and our IMiDs. And we are still learning so much about them, even though we’ve been using them, now we’re getting onto almost 20 years of using these drugs. And I think we heard several talks, two talks today really, about that. About, are there potential markers of resistance that could impact the responses to these backbone therapies?

Lawrence Boise:

You know, Dr Orlowski discussed RAS mutations and how that may actually affect proteasome activity. And I thought that was a really interesting, possible, we’d all love to target RAS for sure. And we do now have a drug that targets RAS, but unfortunately, or for better, or for worse, myeloma patients don’t seem to have the mutation that that drug targets. But I still think it’s very important to understand how the genomics that we are learning about influences even our backbone therapies. I don’t know if you had any thoughts about that?

Paola Neri:

Yeah. It actually, as a follow up as well, I was very intrigued yesterday too. We heard about this immune effect of proteasome inhibitors, of the IMiDs that we kind of knew. But then we try to, we start learning why in combination in PI and IMiDs perform so well, they induce a lot of response in patient, because again, there is an anti-tumor effect, but also immunomodulation effect that is equally important, especially when we talk about combining them together in patients with myeloma. So I agree with you. We are learning a lot by even deeper analyzing the cause of resistance in our patient because then we could combine them in a better way and eventually overcome any of the resistance mechanisms.

Lawrence Boise:

And we also heard about a really intriguing possibility that’s again, I think we’re still in early days of, is understanding how the genes that are involved in the proteasome or in the response to IMiDs are those genes themselves being regulated? Martin Kortüm talked about that. I don’t know if you have any thoughts about that?

Paola Neri:

Yeah. Methylation, epigenomics, I think it’s an aspect that we didn’t actually explore until really recently. And we are learning that it is extremely important to understand even that component, because many genes are on and off regulated by epigenomic events. So I think it’s another- where we talk about what are the best methodologies to understand this factor, I think we have to include the epigenomics or methylomics as another way to study this aspect.

Lawrence Boise:

And not just understanding the biology of it, but also, are these going to be markers that you can use? Can you use methylated DNA, regions of methylated DNA as markers of sensitivity or resistance to these therapies?

Lawrence Boise:

One of the other, again, exciting, I think studies was a new drug, the PIKfyve inhibitor that Dr Keith Stewart discussed and discussed moving forward with. And this was very interesting in that they- he actually first demonstrated this as a potential target actually a few years ago. And now has moved this forward where I think we could see clinical trials in the next couple of years.

Paola Neri:

Yeah. He talked about combination with iberdomide for example, with selinexor, so these are other anti-myeloma drugs that of course we will be interesting to see how do they work together? What is the toxicity profile that we see our patients? So to your point, more discovery brings novel combination for our patients as well. And probably one more thought to just about again, antigen escape, for example. We know which are the targets expressed by the myeloma cells, but now we are learning that the cells overall have a way to escape that. If we target only one element, I show you some cases with the BCMA loss, how important it is now to have additional target. Eventually have dual targeting approaches that in the event, one of the targets gets lost or down-regulated, we have still a way to capture and to target the myeloma cells to induce killing. So I think even that aspect needs to be a further explored, but they are of no doubt. I think in the next session, it will be interesting to see the clinical data for these immune-therapeutics.

Lawrence Boise:

Absolutely. You know, we also, when we think about novel targets, novel targets could be, there’s so many potential targets that we know about, but we haven’t been able to reach yet in myeloma. And one of the real potential opportunities there is through the use of these protac drugs, which target different proteins for degradation, actually working very similar and based on how drugs like IMiDs work.

Lawrence Boise:

Like lenalidomide and pomalidomide. And we did have a talk from, from Dr Shaji Kumar on this, showing a, really what I think I would call a more of a proof of principle protac, and targeting the same molecules that the IMiDs do – ikaros and aiolos. And he really showed some very exciting data with this. Again, I don’t know that we are, whether this will be a drug or not, but the idea that they worked very well and it was much more potent than actually pomalidomide, at least in causing that degradation. So I think it opens an interesting opportunity. I’d love to see more on that. And is, are they also allowing for the targeting of, is it just specific to those or is it also affecting other molecules?

Paola Neri:

Yeah. So how specific it is that I think it will be key to moving forward eventually for the clinical trials. See the specificity they see the also in patient, see in patients how easy it will be to deliver a protac drug that maybe has some issue on transferring in patients. But I think to your point, we may this way target things that would never be possible before. So no doubt that would be a potential new approach.

Lawrence Boise:

And so then finally, you talked about adding, putting BCL2L1 into the CAR-T cells to armor them so that they would be more persistent. I actually talked about the original, which was BCL2 and targeting that in myeloma. There’s been very exciting work, actually done by people like Dr Kumar showing that a subset of myelomas that have the t(11;14) translocation are very sensitive to this. And so we’ve been trying to understand, can we have better predictors of this because even within the t(11;14), it’s only about half of the patients that respond. And so we’ve been working on different ways to do this, and we’ve been focusing on functional approaches to actually measure this. And I think so far the data is promising on that.

Paola Neri:

Yeah. And I’m actually curious because you comment also about the flow panel, what is the best way to even predict response in patient with 11;14? Can you comment a bit more on what component, what marker do you think needs to be there to be able to tell that?

Lawrence Boise:

Sure, Paola, we… This was really based on work that we had published a little less than a year ago, trying to understand what were the factors that controlled venetoclax sensitivity in myeloma. And through several different genomic approaches and looking at gene expression and sensitive and resistant samples and cell lines and patient samples, we determined that it was a subset of myelomas of mostly 11;14, but not exclusively, that express B-cell markers. So a more immature cell than where a myeloma cell is. And we know that within the 11;14, there’s a group that was originally described transcriptionally as the CD2 subtype. And so it kind of fits with that group and there are surface markers that are expressed on B-cells that are not normally on plasma cells, like CD20, and CD79A, and CD79B, and a few others.

Lawrence Boise:

And so we actually, in that paper, developed a flow panel that could be used. Because flow cytometry is used much more commonly in a clinical testing lab than some of the functional tests that we’ve been doing and it may be a way to translate that study worked really well in that. And so we’re still working on it.

Paola Neri:

Yeah. From your perspective having a [inaudible], B-cell phenotype seems to be still a better predictor of venetoclax sensitivity. Why when they become more plasma cell-like, and we have initial data on that regard too. They probably may be a sign of less activity of venetoclax. So something to your point that we need to investigate further, because again, not all the 11;14 respond to venetoclax. It would be nice to have a test that we can easily use and predict the response just based maybe a flow panel.

Lawrence Boise:

Yeah. And I think it’s, that’s what we’re shooting for. So we’ll maybe at the next meeting. So in Myeloma 2023, we’ll present more data on that as well. And so I think that really sums up everything that we heard about. Again, it’s a really exciting morning here of discussion and we’re looking forward to our last session now. So thank you.

Paola Neri:

Thank you.