ASH 2025 | Identifying novel immunotherapy targets in AML beyond canonical membrane proteins

So what we do in my lab is one of the main goals is, for all blood cancers, trying to find new immunotherapy targets, and so that’s for using new modalities such as bispecific T-cell engaging antibodies, antibody-drug conjugates, CAR T-cells. And so the main goal that we’re trying to look at in AML in this case is we know these immunotherapies haven’t worked very well so far. One of the big challenges has been there aren’t really specific targets on the surface of those AML cells that we can use these powerful modalities that will only kill the tumor cells and not critical normal cells within our blood system or other tissues in our body. So one of the big goals in my lab is can we use a technology that we call mass spectrometry-based proteomics, which is a bunch of big words, but really what that means is essentially we can look at the surface of these tumor cells and identify thousands of proteins on their surface and then use computational approaches and other data sets to try to find which ones could be better targets than what we already know. 

What we show in this abstract is we can actually take primary tumors from patients at UCSF who have AML, we can profile the surface of those tumors, and then we did two things. One, we identified a new target called CD209 that is what we call a canonical surface antigen. This is a protein that’s known to be at the surface, previously hadn’t been identified in AML, had been found in other cells, but we think could be a new promising target for AML. But I’ll admit, it’s not perfect. It’s not present on every AML tumor, it’s also expressed on some normal, mature blood cells, we think could still have some side effects that we want to get around. 

So the other big thing we did here was we actually took out this set of proteins we identify in that analysis. We want to focus on the cell surface, but we find a bunch of stuff that typically people think are inside cells. And in the past, everyone thought it was just junk, basically. It’s noise that comes down into technology. We ignore it. Well, we took the hypothesis that maybe one man’s trash is another man’s treasure. And we actually dug into that data. And what we found was that there’s actually a large set, potentially hundreds of proteins that are typically hidden inside normal healthy cells, but in AML tumors actually traffic to the surface of those tumor cells and can be targeted immunotherapeutically. And so several of those we validated, one we’re actually making a promising new therapy against. And we think this actually could unlock a whole new landscape of immunotherapy targets in AML that no one’s ever looked at before. So that’s what we’re really excited about.

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