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CAR-T Meeting 2026 | Searching for the ideal CAR-T target in AML: balancing expression and toxicity
Florian Van Oers, MD, University of Antwerp, Antwerp, Belgium, discusses the challenges of balancing expression and toxicity when searching for novel CAR T-cell therapy targets in acute myeloid leukemia (AML), highlighting the need for an ideal target that combines broad expression with minimal toxicity. Dr Van Oers notes that targets such as CD33 and CD123 have been widely explored but lead to significant toxicity due to their expression on normal hematopoietic stem cells, whereas ADGRE2 (adhesion G protein-coupled receptor E2) emerges as a promising candidate due to its high expression on leukemic stem cells, while sparing normal hematopoietic cells, T-cells, and neutrophils. This interview took place at the EBMT-EHA 8th European CAR T-cell Meeting, held in Palma de Mallorca, Spain.
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Transcript
So with the title, we went for balancing expression and toxicity in AML. Why? Because if you look at the preclinical and the early clinical trials, you see that some targets like CD33, CD123, and CLL-1 are the most explored ones, but also show a lot of toxicity since they are shared with normal hematopoietic stem cells, also mature cells. But on the other side, you have other targets that show a more favorable toxicity profile but are more lowly expressed in a subpopulation of patients...
So with the title, we went for balancing expression and toxicity in AML. Why? Because if you look at the preclinical and the early clinical trials, you see that some targets like CD33, CD123, and CLL-1 are the most explored ones, but also show a lot of toxicity since they are shared with normal hematopoietic stem cells, also mature cells. But on the other side, you have other targets that show a more favorable toxicity profile but are more lowly expressed in a subpopulation of patients. So you see like there is like a balance between something that’s very broadly expressed lots of patients that shows toxicity while others that are more favorable are not that much expressed. So we were looking for what’s the ideal or perfect AML antigen that combines both of them. It sounds quite logical, like something that’s expressed in lots of patients is also expressed on lots of cells. So it’s really the toxicity that’s most problematic, I feel. Because in the end, if you have an antigen that’s expressed in a subpopulation, you could select these patients out. So you can work your way around. But toxicity is more difficult, I feel.
Earlier I mentioned CD33, CD123, and CLL-1. I don’t think they are the most promising, since they have lots of toxicity. So you need ways to work around them. I won’t say they are not promising at all, but you need ways to work around the toxicities, right? For us, in our analysis that we present in the poster, the most promising one is ADGRE2 because it’s not expressed on hematopoietic stem cells, not on T-cells, not on neutrophils, which were our requirements for toxicity. But also are expressed in more than 90% of patients in population-wise of AML patients, or 90% of the AML cells as well, and are also expressed on leukemic stem cells, and those are the cells that thrive relapses because they’re very chemoresistant, but also have self-renewing potential. So we had these five criteria, and they had actually the maximum points on all criteria. So that’s for us the most promising target.
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