iwCAR-T 2023 | AML highlights from iwCAR-T 2023

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Hello, my name’s David Salman from Moffitt Cancer Center in Tampa, Florida.

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It’s really my pleasure to be here with, uh, two colleagues, uh,

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mayor and from Munich in Germany and Roman Shapiro from the Dana-Farber Cancer

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Institute. And we are at, uh, I W CAR T in Scottsdale,

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Arizona in, uh, April of 2023.

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And we really just wrapped up an acute myeloid leukemia session.

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And I think where CAR T has really been that paradigm shift in hematological

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malignancies, it hasn’t quite gotten us there yet. Um,

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as maybe sort of one common message. So maybe Marian, I’d start with you, like,

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what do we need to do to kind of overcome the challenges that we had?

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How do you see CAR T and then bispecifics, um,

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as maybe our path forward for patients that, uh, are lacking options?

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Yeah,

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sort of frustrating that the results so far in Bispecifics and CAR T cells have

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been rather underwhelming if you compare to the B-cell malignancies,

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considering that allogeneic stem cell transplantation has been the most

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successful anti leukemia treatment in a m l.

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So I cannot accept that this will not work,

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but we have to sort of modulate further.

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So I think one of the challenges is identifying suitable target

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antigens. I mean,

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we know that there’s a huge antigen heterogeneity in,

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in intra individually, so that is one of the challenges.

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And I think while we are trying to find a more specific target antigen mm-hmm.

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We probably should possibly accept hemotoxicity.

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I mean, these are all lineage antigens.

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They’re also expressed within the healthy, uh, hematopoietic system.

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And I think, um, maybe if we go a step back,

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instead of replacing allogenic stem cell transplantation,

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one of the strategies might be to integrate CAR T cells into an allogenic stem

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cell approach, part of the conditioning regimen and show efficacy reduced,

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um, relapse rate after allogeneic stem cell transplantation might be one of the

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strategies.

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Yeah, no, no, I agree. I, I think you know,

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that hope for that single antigen car is, is probably not, not realistic.

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And I think you nicely showed in some of your data how heterogeneous it is.

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Not only do you have the marker or not,

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but what’s sort of the intensity of expression.

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And so can we choose some combination and I think what is that combination,

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how many targets that we need so that we can really try to cover a hundred

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percent blast? Actually,

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I think those are key translational data that to me are not,

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not that clear and maybe very different in molecular subsets.

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So a patient with an I D H or a P 53, maybe they have a phenotypic, you know,

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expression that is best to target with with product A, product B. You know, I,

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I think we’d love to have one product that covers everybody, but maybe, um,

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that’s not necessarily realistic. Um, Roman,

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what do you think are some other challenges we have in sort of the cellular

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therapy? Um, you know, uh, challenges that we’ve had a, again,

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in a m l patients? Yeah.

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And you know, there are many,

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Uh, and I think we’re systematically overcoming them, but it’s gonna take time.

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But you know,

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one of the challenges that comes to mind even from our session earlier today are

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the leukemia stem cells.

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And I know there’s been debate in the field about whether, you know,

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these things really exist. Yeah. But you know,

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I’m in the camp that believes that leukemia stem cells exist and uh,

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these are potentially more difficult to target. They don’t cycle as readily.

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There are fewer of them. The, they might not express antigens like for instance,

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what was discussed with nkg two D.

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And so the ability to target those cells that ultimately to ultimately prevent

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even later relapses. You know,

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let’s say you took a hundred percent blast and went down to 0% blast,

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but you did not really eradicate the leukemia stem cell that can perhaps later

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six months or eight months or two years later, uh, result in relapse.

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That would be a key thing I think in a ml. And it’s interesting,

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like for NKG two D as an example,

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I mean there have been studies and groups that have shown that you can

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upregulate, uh,

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ligands for nkg two D with certain drugs like PARP inhibitors as an example.

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There’s a paper that was published in nature a few years ago. Mm-hmm.

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There are strategies that one could potentially implement to combine these

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modalities with cellular therapy to perhaps target the leukemia stem cells.

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Mm-hmm.

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And I think another challenge that we heard is sort of, you know,

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what is the T-cell fitness? Of course, you know, with,

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with autologous products that could be an issue. So, you know, merit,

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I know you’re doing a lot of, you know, work.

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Do you think this is the disease setting, the prior therapies,

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molecular subsets? I mean, what,

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what is the biggest challenge with the T-cell fitness? You talked a lot,

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you know, if we’re just sort of constantly engaging with continuous, you know,

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bispecifics that, you know, we get this exhausted, you know,

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phenotype in the end. So what do we need to be thinking about, um,

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both maybe in CAR T and Bispecifics thinking about the actual T-cell itself?

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Yeah, so first of all,

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I think we need to learn as much as possible from the B-cell, um, field.

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So I mean,

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it has been shown for blin that it works best in the M R D setting low disease

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burden. So I think this is one of the things we, we need to improve.

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We are currently applying bispecifics in CAR T-cell often and,

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and patients there was high disease burden that had received lots of prior

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treatment lines.

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So I think that is one of the things we can probably translate from the B-cell

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malignancies. But then I think there are probably differences and,

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and we know that T-cell, um,

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from m l patients even at initial diagnosis are already compromised,

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uh,

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in function that’s been shown on transcriptional but also on functional data.

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And we know that the T-cell fitness is further decreasing,

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which each prior treatment line,

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we know that T-cell fitness is decreasing a time of relapse. And, um,

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at least from our group,

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we could show that if you are targeting an antigen that is ubiquitously

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expressed and you are sort of giving the bispecific,

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and I think the same applies to the CAR T cells is sort of continuously engaging

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a ubiquitously myeloid lineage target antigen,

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you are further inducing T-cell exhaustion just like in chronic viral

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infections. So I think in that context,

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the target antigen is also contributing to T-cell fitness.

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And in the bispecifics, clearly I would argue that you have to, um,

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apply the bispecific and have then treatment free intervals.

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And that the way you dose your bispecific actually also makes an impact on

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on T-cell fitness.

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Yeah. And I think we have so many moving parts, right? We have target,

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we have T-cell, we have other immune microenvironment issues,

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and I think we need to be very cognizant of that when we’re developing our

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trials. So are we at least in multiple different cohorts trying to answer these

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questions and getting the key sequential bone marrow specimens to maybe help

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answer those translationally? But you know, maybe,

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maybe CAR T cells are not the answer. And I think, you know, maybe Roman,

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you know, is, are NK cells the future, you know, we, you know,

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we’ve chosen the wrong cell with T-cell NK as the answer.

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Maybe if you wanna comment on anything else like gamma delta T-cell or, or,

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or maybe, you know, alternative approaches other than T-cell.

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Yeah. So, you know, uh,

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I think we’re all collaborators and we have a collaborative spirit and we like

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to work together. And in fact, that’s my bias, uh, in this space.

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I think that it’s not the answer to, for leukemia will not be one kind of cell.

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I think that, you know, I’m biased towards NK cells. I work a lot with NK cells.

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I think about NK cells all day. And so, uh,

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I believe that NK cells can definitely form part of the puzzle to attain a deep

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remission. Sustaining that remission is a challenge.

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And I think that ultimately, you know, we alluded to this earlier,

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the success of just bone marrow transplant, right?

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The fact that we can cure 60% of leukemias, at least, you know, that’s at the,

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at the very beginning, if you think about it, you know,

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that’s a success of cellular therapy.

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Can we replicate that in the relapse setting?

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And that with bone marrow transplant, if we look at the graphs,

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there are all kinds of cells in there. Not just NK cells, not just T cells,

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there are monetized their neutrophils.

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There are many other cells in the graph that might be contributing to the

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success of bone marrow transplant. And I think that in the relapse setting,

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you know, if we’re gonna use a car product, uh,

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it’s gonna have to go go into various cell types that will have to work together

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in the NK cell in the early phase NK cell trial that we talked about in the

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session, you know, I, that B P D C Nnk example was just a, you know,

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we were so interested in this, I was trying to understand this better,

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is that how is it possible that we infused a bunch of NK cells and a bunch of

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T-cells ended up in the tumor site where there were no T-cells there before,

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you know,

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clearly there is interaction between the different immune effector cells,

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how to take advantage of that,

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how to make them work together to accomplish a sustained prolonged remission,

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I think is going to be ultimately the way forward.

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Yeah, I think we’ve heard it’s, it’s unfortunately going to be,

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be be quite complicated. Maybe like just taking us home, you know, Marian,

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like what is, what is your sort of message of optimism? You know,

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are we going to have our, you know, immune therapy breakthrough, uh,

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in how we’re gonna get there?

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Yeah. So I,

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I really caution that we conclude from the data we have to be too

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pessimistic, right?

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So I think we really have to remember the success of allogenic stem cell

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transplantation.

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We have all the data also from the B-cell malignancies that platforms do work.

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So I think we are, um,

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need to apply our CAR T cells and biospecific in a different clinical

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scenario. Um, we have to move earlier into a clinical trial.

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And then I think we have to think of combinatorial strategies. I mean,

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you are conducting this trial with also membrane i L 15 unbound,

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we have to think of, of combinatorial of, you know,

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small molecules with maybe CAR T cells,

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bispecifics apply this in a low disease tumor burden early in treatment

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line, um,

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before we kill a platform just because we don’t see efficacy if we apply this

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now in fifth line of therapy. So, um, uh,

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and I also think a ML is a heterogeneous disease,

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so probably one approach is not applicable to all kinds of ml.

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So we also have to adjust to the different genotype and phenotype of a M l

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making it a little more complicated, I must admit. But, um, I think, um,

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there’s so many aspects that are obvious for improvement that I think

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it would be a mistake to give up at this point.

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Yeah, I agree.

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I think this is just a highly endorsed that obviously we need clinical trials

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and actually to get these clinical trials going as soon as possible and maybe

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even, you know, reaching out to our regulatory therapies,

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maybe regulatory authorities, you know, preventing some of these, um, you know,

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kind of very harsh rules on, on, on, on getting these trials,

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getting enough patients treated quickly enough so that we can really try to see

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if a therapy is efficacious or not. But I think with that, you know,

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just thank you, uh, for listening kind of for this a m l wrap up, um,

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at IW CAR T.