iwCAR-T 2024 | The future of CAR-T therapy in AML

David Sallman:

Hi, I’m David Sallman from Moffitt Cancer Center, and I’m joined with my colleague, Dr Fabiana Perna from Moffitt Cancer Center as well. So we really just concluded our AML, CAR-T future directions. And so maybe to start, you know, we have a couple of common antigens: 33, 123, now CLL-1. A little bit of activity, a lot of challenges, including, you know, both from a toxic and sometimes lack of efficacy issues. So I think you’re doing some really great work. You know, can we define new targets in specific patients? So maybe summarize a little bit about what you’re focused on and then maybe what are the next steps. How can we actually translate and get these maybe more personalized and unique approaches into the clinic?

Fabiana Perna:

Yeah, sure. Identifying novel targets in order to extend the promise of a CAR T-cell therapy to AML represents the foremost challenge in the field. So we have utilized an approach where we develop novel pipelines based on mass spectrometry and RNAseq, and the generation of novel computational tools in order to map the cell surface of AML. AML is a complex disease, as you know, there’s lots of heterogeneity, multiple subsets of patients and clones that are genetically defined. So we have utilized an approach where by looking at the specific mutations that frequently recur in AML, we hypothesize that they may eventually shape the AML surface proteome. And, therefore, we have identified some variants of cell surface proteins that may represent some leukemia-specific targets that we would like to eventually bring to the clinic as a novel CAR T-cell therapy targets.

David Sallman:

And so how would we do that? Like what would be these next steps? And I think the challenge is like, what are the timeline of trying to do some of these developments?

Fabiana Perna:

Yeah, that’s a tough question. I think the identification of the novel targets is just the first step. What comes next is developing a CAR platform so that might be suitable for specific targets. So right now, as you were mentioning, most of the targets which are in clinical use are normal proteins that are highly expressed on AML. And therefore combinatorial CAR platforms are very attractive because they may enhance specificity, and so reduce the risk of on-target off-tumor effects, especially on the hematopoietic setting, also preventing the risk of antigen escape, which we see also in the CD19 setting. However, we have identified some leukemia-specific targets that derive from alternative splicing. And while they are very attractive because they may also contribute to leukemogenesis, so not only they have a favorable profile, but they also are functionally relevant. However, they need some optimization of the CAR platform. Because most of the time these leukemia-specific targets are low antigen density targets. And therefore we do need novel receptors compared to conventional CARs that are right now in clinical use. So it’s difficult for me to give you a specific time frame. But, we hope that once the pre-clinical developments are completed, we can launch investigator initiated Phase I clinical trial for patients with AML.

David Sallman:

Yeah. And I think it’s great, right? I think, in parallel, can we come up with new targets on focused subsets of patients? You know, your work is great, Dr Abdel-Wahab I know has some ongoing work in the splicing mutant patients. I think what we’re seeing, at least with the classic targets, there can be some patients that get excellent responses, patients eight years cured from disease who got a CAR-T therapy. I think this is kind of where our field is going right now. And this in summary is, I think, is it a factor of when we’re treating these patients, too relapsed/refractory, too much high burden of disease. So what I’m somewhat optimistic by is just starting now, both with our PRGN CD33 CAR, with the CD123 CAR concept, actually the allo CLL-1 CB-012 will also eventually target these MRD. So I think we’ll see, can we eradicate MRD? Can this be a bridge to transplant or eradication of MRD in the post-transplant setting? I think that may be a big hope, at least for the single antigen. But I think what you alluded to, I really want compound CAR to happen now. I mean, if we had the data that was out of China with the CD33 CLL-1, seven of nine responses, we would have ran a pivotal trial a long time ago. So I’m really hoping one of the companies will really jump forward that quickly. I do think we have a lot of hurdles, even working with regulatory on how can we more quickly get these patients a chance because again, most of these patients being treated have no really options of therapy and actually quite limited clinical trial settings, especially in the post allogeneic stem cell transplant. I thought a really nice talk was again out of the UPenn group, Anand Bhagwat and Saar Gill, discussing it today that the cytokines that these cells are producing are now further hampering the actual activity. And so I mean I guess some pessimist is this just too complex. But I guess how do we, being in the lab, we have the target, but how are you also looking at the different immune cell subsets, the impact both autologous allogeneic. How do we need a better characterize this maybe with our ongoing efforts?

Fabiana Perna:

I mean, definitely, in addition to the lack of targets, the contribution of an immunosuppressive microenvironment represents another major challenge for developing a CAR therapy to AML. I think there are emerging studies suggesting that the microenvironment regulates the CAR T-cell function. So the way I see it is kind of two way around. It’s like the CAR regulating the myeloid suppressive microenvironment, but it’s also the compartment that eventually further impacts the CAR T-cell function. So definitely, when we think forward designing a trial for AML, I think ideally we should aim for a curative approach. So I would prefer that compared to a bridge to transplant. We should definitely look for a potentially leukemia-specific target in a genetically defined subset and take into consideration the contribution of the microenvironment. So eventually, as we are thinking of more combinatorial targeting, we can also think for combination therapies where we not only target the malignant clone, but actually we have enough resources basically to combine additional approaches that may eventually also address that challenge.

David Sallman:

Yeah. And I thought also it was nice today, Nirali Shah gave sort of an update on the parallel approaches in pediatrics. And especially in AML we’re still a little bit more in our infancy. I think we can actually all potentially work together and really hopefully move that field forward both in pediatric and adult populations in parallel. And, I think, at least in my mind, I’m optimistic for the future. Again, we have all of these hurdles. But maybe with all of these different approaches, you know, can we have our first CAR-T or cellular therapy for our patients with acute myeloid leukemia and potentially myelodysplastic or other related diseases like chronic myelomonocytic leukemia? You know, let’s hope but again, I think we all need to highly push these clinical trials to move forward as quickly as possible.

Fabiana Perna:

Yeah, absolutely. I mean, it is very important to, you know, implement the investigation in the myeloid settings not only for myeloid malignancies, which, of course, you know, include also MDS, but also because the myeloid compartment contributes to cytotoxicity as well in the lymphoid settings. So I think it’s very important if we have a way to target that as well.

David Sallman:

Yeah. So I think the pitch is just for both the community and pharma to, you know, help us move these trials forward as quickly as possible. But thank you for listening today. Thank you for discussing, Fabiana.

Fabiana Perna:

Thank you.