iwAL 2023 | Transplantation & immunotherapies

Hello, I’m Charlie Craddock from Birmingham in the UK, and it’s a real pleasure to be joined by David Sallman from Moffitt in Florida, Mark Levis from John Hopkins, and Nelli Bejanyan from Moffitt.

We’ve just had a really fantastic session covering some broad areas around how we think about improving outcomes in patients with AML through distinct and varied immunotherapeutic strategies including transplant. And David, I want to just start with you really to give us a state-of-the-art with where we are on CAR-T cell development in AML. It’s an area of active interest at the moment.

Yeah, I mean, I think at this wonderful conference, I think we’ve heard a lot about exciting breakthroughs, you know, throughout, but unfortunately a majority of patients are still ultimately relapsing and really having a novel cellular therapy like we have in other hematologic malignancies, I think is really paramount. You know, to all of us, I think we’re still in our infancy stages. I think there are, you know, several targets. The three main ones right now being CD33, CD123, CLL1, that are starting to move, you know, farther along in clinical trials. And finally, some of them are actually to expansion to where we can really see what the efficacy signal is, both with and potentially without, you know, salvage transplant, second transplant, you know, DLI.

So we are seeing responses. I think the challenge is the response rates have been low, the durability has not been great. And so the big questions is why is this? Are we treating the wrong patients at the wrong time? So are these patients that are too heavily relapsed/refractory, T-cell fitness that’s significantly impaired, or is this a target issue where we know that unfortunately there’s a ton of heterogeneity and are we really missing a majority or a significant proportion of blasts? And I think those are the big questions. I think we are seeing anecdotal great responses. I do think, you know, moving the field forward is going to be out of the box approaches. So I do think compound CARs with OR-gating strategies, where again, they will activate with seeing multiple different antigens, is probably gonna be the key going forward. I think with that consideration, there may be increased toxicity, especially myelosuppression, and so I do think thinking about that in tandem, designing early trials may in CR1, MRD-positive disease and getting them to transplant in the best optimal remission is where we’re going. But again, I think this is going to take us actually years and not months to really potentially move that field forward. But again, optimism is, is always important.

Mark, some general observations maybe about the patient population that we should be thinking of most eligible for this approach?

Well, again, I’ve harped on perhaps not using the TP53 complex karyotype crowd or carving that out distinctly. because I think we lose a lot of therapies when we, I think they’re two different diseases and often our benefits are on the margins and the addition of a population that is so dramatically different.  So if we have to think differently about the disease, but then, I think it becomes easier if we get an agreement to do that. this is my – I’m convinced this is what’s weighing down a lot of trials right now, is that population as as sorry as we are for them, we’ve got to carve them out of the field. I think, I think relevant to that, the challenge biologically, they’re a hyper proliferative, non increased blast patient that you have potentially time, but then a lot of these patients are getting into the early, you know, CAR-T studies and is that negatively impacting? So that, I think that’s a huge, important consideration.

So, David, you published on the immunosuppressive, bone marrow microenvironment in P53 mutated. I mean to what extent do you think there are host issues here, either around T-cell numbers or fitness, or possibly an immunosuppressive microenvironment that might abrogate an effective a CAR-T?

Yeah, I mean, I think that it speaks, again to Mark’s point and then, you know, why are these patients not responding? And I’m not aware of any P53 mutant patient that has responded to any cellular therapy, again, outside of something that was, you know, immediately to transplant. So we do know the immune microenvironment is dramatically different. It’s a very exhausted anergic phenotype, potentially inflammatory, at the same time. And the scary part and this is some data out of, of MD Anderson where they did single cell cytokine profiling, looking at poly functionality of T-cells, and even in P53 patients before they ever got therapy, there’s really this profound dysfunction. So I do think for P53, I’d be much more thinking about an allogeneic type product because of this impaired T-cell, but then even with that, I think we need to think about, you know, potentially some of the direct immunosuppressive mechanisms of the malignant stem cells in that population.

So it’s gonna have to be an out of the box approach, probably an allogeneic approach. But again, I think carving it out and thinking about a very specific platform for that group. And again, the bar is low, so I think if we had a signal there and we could see deepening of remission, which again, several of us have shown, you know, translating to ultimately improved outcomes of transplant, maybe a key consideration. And I think FDA was open to potentially carving it out.

And then just switching gears, Mark, you, you, your work’s been pivotal in establishing pre-transplant MRD as a prognostic indicator when patients have proceeded to transplant. And I think it was identified at the meeting, you know, that one of the really hot questions that is out there at the moment is, is it possible to ask a question as to whether targeting pre-transplant MRD might be a route to reducing relapse post-transplant, improving transplant outcome?

It’s quite a challenging area to develop clinical trials, and I think there aren’t any at the moment. So some general comments. So First, there’s sort of two sides of the MRD issue, the regulators brought up, no, we want this thing standardized in all our minds, we believe it. Okay. We believe we’ve designed an assay that easily can be standardized. So we actually have two, we have NPM1 and FLT3 that are kits that are reproducible. They’re gonna get the same result anywhere in the world with basically following the recipe. That’s a huge tool. We want to validate the, we validated NPM1. We’re probably going to succeed in validating FLT3-ITD. But as you say, what do we do with that now? Can we eradicate it? And, and how so and so that elicited as you know, quite a lot of passion and ideas being flung out.

I still do like the concepts that were brought up, focusing on the less intensively treated patients. Those are the patients that are gonna have higher levels of MRD. NPM1 mutant patients do really well regardless. And so that’s a tough population to improve upon. But the older patient, not so much. We know this, we’re using aza-ven, we’re very pleased with ourselves, but still not, we have far to go. And that’s the population, I think, we should be saying you’re MRD positive with either NPM1 or FLT3, we’re going to use a FLT3 inhibitor or a menin inhibitor or something else randomized at the start. Because those patients going to transplant, if you do intention to treat at randomization, you will lose some of those patients. I think that has the potential to get us an answer and maybe use MRD to benefit patients, come up with a new therapy.

And Nelli, you’re a coalface transplanter. Any comments about how you might design such a study? Or what do you think might be targets?

Some of the studies can be designed actually to use intervention in a context of allogeneic transplantation. Either that would be optimizing further the conditioning regimen, and that can be additional drugs or cellular therapy approaches incorporated there. Or doing something consolidative after allogeneic transplantation. I believe more in cellular therapy, I’m a transplanter, but, because I know that AML most of the time can be cured with cellular therapy and standard being allogeneic transplantation, if we can learn more about subset of cells that can benefit patients in terms of enhancing further the GvL effect without compromising, their outcomes in terms of increasing GvHD that would be type of a strategy I personally would look for in the context of allogeneic transplantation.

So let’s just talk a little bit more then about DLI, because you know, we know this is a really, it is pretty well tolerated if you get your dosing schedule right and it, we all know that it can be highly effective in patients who are MRD positive or cytogenetic relapse. And before I came, David, we had a lady with cytogenetic relapse, P53 mutated MDS, who just has had the most fantastic response to DLI. And then of course we have other people stacking up who don’t. So the challenge, I guess, Nelli, and perhaps you could give some thoughts on this, is how do we optimally employ cellular therapy post-transplant? What are the exciting areas?

I’m more than happy to comment on that. In regards to a conventional donor lymphocyte infusion, obviously there’ve been concerns there in terms of increasing risk of graft versus host disease. In some studies, it’s up to 40% or 50% of the patients developing acute or chronic graft versus host disease. That definitely increases the morbidity and affects quality of life of the patients as well.

However, though, in the high-risk setting, not only in prophylactic, but also preemptive, at least retrospective number of studies from different institutions and registry data are supporting the use of donor lymphocyte infusion post-transplant. We need to still learn more about the dosing schedule and the frequency of that. And who are the patients who benefit more with that strategy, is that the patients who are intermediate risk disease patients or these adverse risk disease patients benefit as well? We don’t know the answer for that because of the limitation of heterogeneity of what is being reported so far.

But also there we can farther look into strategies that are, not just conventional DLI with lots of various cells, including alpha-beta T-cells that are associated with higher risk of GvHD like our group specifically is exploring doing donor lymphocyte infusion focused on gamma delta T-cells. So freshly collected from the allogeneic donor, the same donor that, patients receive stem cells from. And then we are infusing for purpose of reducing the risk of relapse in adverse risk group of patients by ELN classification and hoping that strategy will be effective but yet need to be determined. We are currently looking into safety data of that and most importantly why gamma delta T-cells because they have MHC independent cytotoxic activity against AML, but more so they don’t cause graft versus host disease. So we can give more products and higher numbers as far as we can successfully expand this.

Once you’ve established safety and you’ve got your dosing schedule right, tell us what the randomized study might look like.

The randomized study should be basically exploring this approach using its consolidative, basically expanded gamma delta T-cell infusion after allogeneic transplantation. And the standard needs to be standard allogeneic transplant without planned intervention per se.

And in this context, give a shout out to my colleague in the UK, Dr Victoria Potter at Kings who has randomized, I think it’s 160 patients to a study called PRO-DLI, which is actually looking at prophylactic DLDI, patients transplanted for high risk AML in CR1. And it involves rapid taper of immunosuppression and prophylactic use of DLI against a more controlled approach. And I hope that study’s gonna be reporting next year.

And what’s the MRD monitoring in that study?

Yeah. No, meticulous MRD monitoring if there’s a molecular marker or with flow.

And then finally, perhaps Mark, if I could just turn back to you, you presented a bit of an update on some of the MORPHO data, which you showed at EHA and you reflected perhaps on two or three lessons that might have been learned or some more general observations. Perhaps you could close with those thoughts.

Sure. It always comes down to azoles. Now, in fact, it’s a very simple answer. You asked, how would we have designed the trial differently? We would’ve said, only give azoles as indicated, because this is a theme emerging with gilteritinib and quizartinib. They have azoles. Mould-active azoles have their uses. you’ve got to use them judiciously with these drugs. You will get significant myelosuppression and toxicity and completely counter any benefit if you use them indiscriminately. And so, I think the lesson from MORPHO broadly is twofold. Give post-transplant gilteritinib to patients who are MRD-positive and use azoles judiciously. And, things can work out just fine.

Great. And we are looking forward to updated data sets. Thank you. Thank you all three. That was a great discussion.