Hello and welcome to the wrap up of the immunotherapy for AML session. We’re here at the 2022 iwAL meeting in Nice, France, and my name is Saar Gill. I’m an associate professor of medicine at the University of Pennsylvania. So I’m joined today by two of my colleagues, Dr Marion Subklewe from Munich, and Dr Amer Zeidan from Yale.

I would like to start off by asking Dr Subklewe to tell us a little bit about her thoughts on immunotherapies in AML, the challenges and the progress today.

All right, that’s challenging question. So, I think there’s different parts which have sort of hampered to translate the success of T-cell based immunotherapy from B cell neoplasias to AML. And there is the challenge of finding a suitable target antigen. And I think the challenge not only finding specificity for AML in contrast to the healthy hematopoietic system, but it also might translate into antigen sync. And also continuous… signalling, thereby inducing or supporting T cell exhaustion. And the other aspect, I think which is important to acknowledge is that we do know that T-cells in AML patients, particularly in relapse and after several prior treatment lines, are dysfunctional.

So if we apply bispecifics or do autologous CAR-T cells, the compartment is hampered, and probably we need either allogeneic, T-cells, or we need to do combinatorial strategies to increase T-cell function and probably also use these kinds of modalities in an earlier clinical setting.

Thank you. So if T-cells are dysfunctional in AML, do you think we’re barking up the wrong tree? Should be going after a different cell type? I’ll start with you, Marion, again, and then I’ll go to Amer.

Right. So, you know, I think from the allogeneic stem cell transplantation, we still know the T cells can do the job in AML, so I’m still sort of attached to the T cells, and I believe that the T cells are able to do the job in principle. But there’s very interesting data also utilizing NK cells, and it has to be seen if that is a more suitable population but I don’t think we can fix it to NK or T cells, but it has to be considered in which setting we’re actually using it from time point. We’re harvesting these cells, but yeah, so, you know, I think from allo, we know the T cells still are working in principle. Yeah, I agree with you, for what it’s worth. Amer, what about you?

I agree. I mean, I think there are multiple layers of evidence that suggest, you know, immune activation should work in AML. As Marion said, allogeneic bone marrow transplantation is the most potent, really, anti-leukemia activity we have. Also, I think there is some layers of evidence that chemotherapy does not only work by directly killing the cells, but also by some immune stimulation. We know not everybody with MRD positive disease relapse, some of those patients will clear the MRD months after receiving chemotherapy, which is probably due to some immune system activation. So I think the issue in my mind is more how or did we figure out how to optimize our use of the immune system in a way that helps the patient? I mean, I think you have to be optimistic because this was already figure to a large degree in lymphoblastic leukemia. it’s an easier challenge there because you can effectively eliminate all the B cells. And, you know, you still can live relatively normal life. And the myeloid compartment is going to be challenging.

But I think there’s some incremental knowledge, and at the same time, there are significant challenges. We are still kind of learning our way in, but I am very optimistic about the future.

So you’ve done a lot of work on on checkpoint blockade in myeloid malignancies. What do you think are the learnings from that? What have you taken away from it?

I think this is also I think, another area where I always thought that you know, if we’re going to get a breakthrough with immune checkpoint inhibition probably would be in our cancers, in hematologic cancers, is just because of the bone marrow transplant experience. But this started actually in solid tumors and, you know, and tumors that we generally thought our immunogenic melanomas and renal cell carcinoma. But then subsequently, this has expanded to so many different solid tumors have improvements basically, lung cancer, head and neck, several subsets, bladder cancer. So I think we started to test that in leukemia patients, and I think we quickly realized several things.

One of them is that I think doing these drugs as monotherapies generally does not seem to work, for whatever reason. They do work in solid tumors as monotherapy, but not in our malignancies. I think the second thing is that using them later in lines of therapy similar to what Marion was saying, I think that the immune system is exhausted to a degree that sometimes you just cannot stimulate it enough to eradicate the tumor clones. I think the biggest challenge from all the studies that I actually have conducted is many investigators still don’t have the same degree of familiarity of how to manage the immune-related adverse events and how to distinguish those from complications we often see in leukemia patients. For example, you know, we often see fungal infections, and how can you tell Is this pneumonitis or or if this is a fungal pneumonia, another thing, getting biopsies, you know, in solid tumors it’s easy to biopsy the colon or the lung. If you suspect that this is an immune-related adverse event. In our patients, they have no platelets sometimes. So I think a lot of that is creating some challenge. We have studies that show that this is feasible. But since our doctors generally don’t use immune checkpoint inhibitors because they’re not approved for any indication within myeloid malignancies, I think it takes time to get a good sense about when to use steroids not to use steroids, when to re-challenge. So I think all of these factors have somewhat affected the field, but we’re certainly starting to see, especially with what I quote, second generation immune checkpoint inhibitors, CD47, the TIM-3. Those might be different than the classical CTLA-4, PD-1, PD-L1 ones.

I guess correct me if I’m wrong, but I thought to date the most interesting results with respect to responses in AML, were in the post-allo setting. Were some of those trials that you’ve done in post-allo, or were they?

Correct, so this was actually one of the trials that really captured, I think a lot of attention in the field. This was a Dana Farber single study or single center study in which they have given ipilimumab, the first anti-CTLA-4 to be approved in melanoma as a monotherapy post-transplant setting. And I think the two main features of that study is that five patients with relapsed AML achieved full responses, which again, I think, is a very good proof of principle that these interventions can work. However, you have to know that most of those responses happened in extramedullary disease. They were not bone marrow clearances, which again, I think raises the question is the tumor micro-environment different between the bone marrow? And maybe we are not just able to manipulate the bone marrow as much as we can with extramedullary disease? I think the second thing which often comes in why people are hesitant to use immune checkpoint inhibition, is, you know, is the concern about graft versus host disease, worsening or induction. But I think the collective experience I don’t think this is a major concern. I think most of those patients, unfortunately die from their disease, not from GvHD and I still think those immune checkpoint inhibitors should be explored more aggressively and not worry too much. Of course, we have to monitor for it, but I don’t think that has been shown to be prohibitive in any trial.

So we heard about, CAR-T cells against CD123 and CD33 as well as compound CARs against CD33…and 12.. though I know the latter one wasn’t either of your work, But I’m curious what you thought about that? Can I start with you?

So, I mean, I think CAR-T cells, we have to be aware there are two different strategies. So one strategy is trying to follow to substitute allogeneic stem cell transplantatioon. And there we have the challenge of increasing specificity, as currently all the targeted antigens, most of the target antigens, and that the ones you mentioned are myeloid lineage antigens. Right? And we very likely wipe out the healthy hematopoietic system. But I think in principle, this is probably where we have to show efficacy first, that in show proof of concept that CAR-T cells are able to eliminate the AML cells and as a side effect, also the healthy hematopoietic system and then salvage with allogeneic stem cell transplant and reduce the relapse rate. And actually, we haven’t shown that yet, so this is sort of the first challenge. But ideally, if we think of the average age of AML and how many patients we are actually transplanting, I think we need strategies to be more specific and mimic somehow some of the success of allogeneic stem cell transplantation and trying to omit healthy compartment. And I mean, we saw some strategies also today that are trying to be more specific. But as I said, I think as long as we’re not doing our job even with the salvaged allogeneic stem cell transplantation, there’s still some way to go until we are successful without an allogeneic salvage.

I wondered a little bit whether that, maybe this will be my last my last talking point with you. But I wanted a little bit whether your strategy of checkpoint blockade removing the breaks from the immune system might be nicely combined with some of the things that you talked about, Marion, for example, neo antigen specific T-cells that you talked about the WT1-specific T-cells, maybe T cells either engineered to recognize HLA presented antigens or T-cells that, we didn’t maybe talk about it so much today.

But T cells expanded against tumor associated antigens like you know, other than WT1… for example. So I wonder whether maybe it’s the last question. You think that it might be useful to do that? Because otherwise, when we do checkpoint blockade without T cells of known specificity, we don’t really know what the T cells are supposed to be seeing.

I agree with you. I don’t think immune checkpoint inhibition is going to work as a monotherapy. I mean, it has to be combined with other things now, whether you combine it with other targeted therapies, you know, we discussed some data, for example, in combination with venetoclax or with IDH inhibitors, or you could combine it with other immune modalities. Now there has been some data, for example, about combining with bispecifics or ADCs. I do think it’s intriguing, you know, to think about combining also with, some approaches related to CAR-T cell therapies. I think my main concern continues in general, with CAR-T cell therapies that most of the success has been in tumors where you can get rid of the normal counterparts completely, like B cells. And I continue to think that, you know, we often hear about antigens that are present on the leukemia stem cells, but not present on the hematopoietic stem cells. And I, each time, like some of that comes from the lab to the clinic, doesn’t always pan out. And I think this is going to be a big challenge. And, so I think the big picture, I’m not sure that CAR-T cells by themselves could be a cure. I mean, it could be, I think, a good bridge for, like, very refractory leukemias to transplant or some. But I think the biggest challenge is going to be how to use them in a way that is sustainable. So you have suicide genes or some other way, so that you can get rid of that myeloid depletion that is just I think it’s going to be a problem.

I think we’re making some progress in cytokine release syndrome, and ICANS control, all of those aspects. But I think the main issue in my mind is how do you actually target the leukemia cells without depleting the myeloid compartment?

Yeah. Okay. Well, thank you. I think I’ll sum up maybe my impression, which is that while to date, we’ve had, slower progress than in the ALL field, I think that we’ve seen even today measurable progress albeit modest in some cases. But at least when it comes to new concepts, when I think even learning from one’s mistakes or from one’s lack of progress, at times does does help us in the future. So I hope that as we meet again, hopefully in a year, hopefully in a place as nice as Nice, and that will have additional progress to report. Thank you.