iwAL 2025 | Immunotherapy in AML: translational insights and promising avenues being explored

Marion Subklewe:

Welcome. My name is Marion Subklewe and together with my co-chair we just had a fantastic session on immunotherapy in AML. We are reporting from the International Workshop on Acute Leukemia here in Washington DC, and I’m really happy that the speakers are joined for now, summing up what we just discussed. And I will start with handing over to Nelli from Moffitt. She gave a talk, giving a short overview on the CAR T-cell activities we have in AML, and also reporting on a really fascinating clinical trial on gamma-delta T-cells in AML. So maybe you want to introduce yourself and give a brief summary. 

Nelli Bejanyan:

Yes, I’m Nelli Bejanyan from Moffitt Cancer Center. And I was talking today about the CAR T-cell therapies in AML, unfortunately we haven’t had much successes, unlike CAR T-cell therapy for lymphoma or multiple myeloma. So there are various reasons for it. Certain targets are very heterogeneous and there is an issue of resistance associated with CAR T-cell therapy, including also trying to find out how we can work in immunosuppressive microenvironment to improve efficacy of CAR T-cell treatment, etc. I was specifically talking about gamma delta T-cell immunotherapy, as a potential novel therapy approach for treatment of AML. The trial that we conducted at Moffitt Cancer Center, that was a Phase one trial that is a relapse prevention trial for high-risk AML patients who are receiving allogeneic stem cell transplantation, and at a high risk for relapse. Approximately 40 to 65 percent of these patients are MRD positive or with TP53 mutation. All the patients had the adverse risk AML by genetic classification based on ELN 2022, and they received reduced-intensity conditioning transplant. Basically, ultra-high risk AML patients that are expected not to have good outcomes. We infused gamma-delta T-cells from the donors that donated stem cells. We expanded these cells in vitro and infused 60 to 90 days after allogeneic transplantation. As a result, we found out that these high-risk patients achieved remission except for two relapsed post-gamma-delta T-cell immunotherapy with relapsed risk being only 17%, and all of them completed their one-year follow-up. There is remaining MRD negative remission. So this was also relevant to some of the patients who had MRD positivity post-transplant with TP53 mutation and are expected to have almost 100% recurrence risk. And after gamma delta T-cell infusion, they cleared their MRD. One of the patients is two years post-transplantation doing well in MRD-negative CR. The other patient was 8 months post-transplant, unfortunately died of sepsis. So we are hoping to further pursue this. This is obviously phase one, although promising results, but needs to be efficacy tested in subsequent trial setting phase two, and we are hoping to move forward and conduct phase two trials. 

Marion Subklewe:

Yep, so really promising data. Congratulations. Just one sentence, sort of the trial is closed and you’re hoping to expand or can you just give an update where do you stand? Are you still recruiting? 

Nelli Bejanyan:

No, the phase one trial is closed. It’s funding was available only for phase one and hoping to secure funding for the subsequent stage. 

Marion Subklewe:

So then we had another talk, more exploring NK-cells in different formats. So it’s a pleasure that Jeff Miller is here and he’s going to give a summary of his talk. 

Jeffrey Miller:

Great. Thank you. My name is Jeff Miller. I’m the director of the Masonic Cancer Center at the University of Minnesota. And I’ve really spent my entire academic career studying the biology of NK-cells in different malignancies. And we really started off in AML. We’ve treated almost 400 patients now with various degrees of NK-cell infusions, starting off with individual donor NK-cells and now moving to allogeneic off-the-shelf cells. Our favorite platform for this is really using an IPS technology that you could do multiple gene edits. You could put in CARs, you could give them exhaustion-resistant gene edits, to make them most favorable. And we’ve done this, and we have ongoing trials in AML that now have four gene-edited NK-cells that are going to be starting in the clinic towards the end of the year. The other thing that I contrasted in my talk is that cell therapy is still complicated. Allogeneic cells have been debated for a very long time. And we have proof of concept in the ALL world with blinatumomab, which really motivated us to start looking at NK-cell engagers. We’ve designed an engager that we call a trike that has three functional domains, hence its name, to really engage the NK-cell surface, to bring a co-stimulary cytokine signal IL-15 to the immune synapse, which really expands the immunologic response and allows specific targeting, even in a tremendously immunosuppressed cancer-bearing patient. We had 12 patients treating on a dose escalation trial with a first-generation trike, and I highlighted some of the clinical results from that. And as we’ve developed things in the lab, we found out that certain engagers work a little bit better. Now working on an engager that binds to the NK-cell using a camelid VHH or nanobody region. And we’re now in clinical trials with that molecule as well. And we hope to dose escalate and present new data for that trial at ASH this year. 

Marion Subklewe:

Yes, thank you so much. I also think it highlights that we now have the technology to build and modulate whatever we think of. We really need to understand also the biology, what is most useful, right? But there’s sort of no limits to what we actually can do or build, right? It was costim and these kind of things. So to sum up my talk, I think I want to share three thoughts that were integrated in my presentation on T-cell-based immunotherapy. I think an interesting and really groundbreaking development is the data that has been shown at several conferences where hematopoietic stem cells are genetically engineered and then used for transplant and followed by all kinds of immunotherapy, you could apply CAR T-cells, ADCs, monoclonal antibodies, or T-cell engagers. And it has been now shown for C33 through CRISPR-Cas editing that you can actually generate these stem cell grafts, they do engraft very similar to a conventional graft, and then you can give gemtuzumab six or eight weeks after engraftment and show that this is safe, no drop in neutrophils or platelets, and that has been shown and also translated into a setting with allo CD33-directed CAR T-cells. So I think an exciting avenue, clearly a bit complicated, but might be a new path for getting successful CAR T-cell therapy in the clinics, and there are other target antigens like CD45, FLT3, CD123 that has been at least preclinically shown to be interesting and successful target antigens. The other aspect I’d sort of like to highlight is that in AML, we also need to think of combinatorial strategies, that also applies for immunotherapy. So I’ve shown examples that there might be a benefit of using this in combination with VEN-AZA or use novel CAR T-cell designs. Again, you need to understand the biology. There has been just a very small publication of five patients, but I think really interesting with CLL1-directed CAR T-cells that are secreting IL-18, sort of paths to overcome some of the immunosuppressive microenvironment of the bone marrow. And I really think that we need to think of smart combinatorial strategies to enhance efficacy. And the third point I’d just like to highlight, I was proud of it, that there’s a consortium highlighting on reporting of CAR T-cell trials in AML. And I think it’s really important in AML in principle, with always smaller cohorts, that we try to engage and report so that we can use data from different trial sites. I think that’s also one aspect I wanted to stress. And I think another topic, and now I move to our next speaker, John DiPersio, is toxicity efficacy and the topic of CRS in AML. Really interesting talk. It generated most of the questions in that session. And maybe John can sort of summarize some of his key findings. 

John DiPersio:

Thanks, Marion. So I’m John DiPersio. I’m from Washington University in St. Louis. And, you know, my talk really focused on some of the toxicity aspects of CAR T-cell therapy, you know, as it applies to not only AML, but all CAR T-cell therapies. And so I think I introduced the topic by saying that we still have a lot to do with improving efficacy in immunotherapy for AML. And everybody on the panel really had some very interesting insights relating to how we can do that best. But in the end, you know, especially with certain cellular therapies, particularly T-cell therapies, there is a risk of a number of significant toxicities which can be mild, moderate or life-threatening such as CRS, ICANS, and HLH. And so we’ve been sort of interested in the biology of CRS and to sort of explore that, we’ve developed a very simple preclinical model using human T-cells transduced with a CAR at target population that’s luciferase labelled so we can track them in a dish, and myeloid cells which produce actually all of the cytokines that we think are the surrogate marker of CRS. So we have sort of an in vitro, in the dish model of in vivo CRS. And we’ve been exploring ways to inhibit the production of IL-6, the surrogate marker of CRS, without altering CAR T-cell function and the ability of CAR T-cells to kill the target population of either AML cells or lymphoma cells, depending upon what the CAR is. And the studies really took two major directions. One, we identified kinase inhibitors that by themselves or when combined actually inhibit IL-6 production by these myeloid cells dramatically without altering CAR T-cell function in our assay. We’d have to prove this in clinical trials. And I should say that we’ve done some very early clinical trials validating the data in the laboratory. So I think that’s done. Small clinical trials are important, but they need to be validated by bigger studies. So that needs to be done. And then the other pathway that we sort of exploited was CRISPR gene editing. And so in one case, we looked at small molecule kinase inhibitors to block CRS, in the other, we looked for pathways and genes when knocked out would block CRS without inhibiting CAR T-cell function. And we identified a specific pathway and T-cell activation marker called CD40 ligand, which is secreted but also surface bound. And we showed in knockout studies and neutralization studies that when you block that CD40 ligand in a T-cell, it blocks the production of IL-6 in myeloid cells. And so there is a pathway forward using either knockout technology, which is expensive and complicated, or neutralizing antibodies, which surprisingly, there are very few of these neutralizing antibodies because there’s been some toxicities with these antibodies due to thromocytopenia that we’re interested in sort of working on. But that’s a way that we could sort of reduce CRS as well. And then the other pathway, of course, is the gamma interferon pathway, which was implicated by some of the small molecule inhibitors that we identified. And also, there are several groups in the world looking at antibodies to gamma as a way of blocking CRS, and so we’re anxious to see how those trials end up as well. 

Marion Subklewe:

So I think you can already hear that sort of the leukemia microenvironment cytokines modulate also T- and NK-cell function. And it’s also been shown that certain genetics actually are associated with different types of immunosuppressive leukemia microenvironment. And that somehow brings me to the last talk of Ann-Kathrin Eisfeld. She talked about loss of the Y gene, and it also has some impact on the microenvironment. So maybe you can summarize your talk. 

Ann-Kathrin Eisfeld:

Thank you for the great loop-in Marion in here. So I’m Ann-Kathrin Eisfeld from The Ohio State University. Really also focusing on the microenvironment, as Marion said, but coming from a little bit different direction from an old paradigm that, it’s known that just people in general can can lose their Y chromosome, which is a male-defining chromosome, over age, over time. And for decades and decades, it was thought that this is more of a neutral event, it wouldn’t matter, because there are not many genes on the Y chromosome, and many of them are kind of duplicated on the X chromosome, of which females harbor two copies. Over the past years, there have been increasing interest in looking and revisiting this for a couple of reasons. One reason really being that male patients generally do worse than female patients almost in every disease. And while we like to believe that this is because males don’t go to the doctor and they don’t follow the instructions, they don’t listen to their wives as much as they should, there has been like some very, very intriguing signs showing that the loss of the Y chromosome in solid tumors may alter the immune microenvironment and response to chemotherapy, and especially in solid tumors also the response to immunotherapies. So since we love to look at chromosomes in the leukemia setting, and we know how important these changes are, we started to sequence patients who had their only change in the chromosomes, male patients who lost their Y chromosome and compared it to patients, to male patients, who still had their Y chromosome and could see that they were very distinct in the way how the leukemia was acting. The first thing we saw is that the Y chromosome was only lost in the cancer cells themselves, not the microenvironmental cells, but it had a tremendous effect, what we call intrinsically and extrinsically. Intrinsically, that there was a deregulation of the immune response, inflammation pattern. And also extrinsically, more from the innate immunity perspective, that the cell populations differed in here. And together, that led, when we were revisiting the survival outcomes on this very clean cohort, is that the patients who lost their Y chromosome had actually very good outcomes. Almost like way better even than female patients in here. And when we were looking at all patients and all male patients, where genes can be expressed or not expressed for various other reasons, those males who also had lower expression of these Y chromosomal genes did a lot better than the counterparts that still expressed those genes. So we were very excited by that and think that there are multiple avenues to further follow up on it. 

Marion Subklewe:

So thank you very much. So hopefully by sharing some of our talks and thoughts, you can see the excitement that we had in a very translational session, and I’d really like to thank all the speakers for taking the time to sum up the talks. Thank you for listening, and happy greetings from Washington DC.

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