ASH 2024 | ST3GAL1 as a novel biomarker of lack of sustained MRD negativity in multiple myeloma

So the subject of my ASH presentation was that the increased expression of a gene which is involved in expressing sialic acid on the cell surface called ST3-Gal1 is associated with increased risk of MRD resurgence and inferior progression-free survival in patients with multiple myeloma who were transplant eligible who were treated on the Cassiopeia study, which was a large, randomized trial that compared VTd with VTd-DARA as induction, and then patients had a transplant, and then consolidation, followed by maintenance therapy or observation. So, I mean, the background to this is that I’ve had an interest in sialylation, probably going back about 14 years or so. And we first discovered that sialylation is overexpressed in multiple myeloma and is associated with inferior progression-free survival and overall survival. And initially, this related to genes which were involved in generating what are called selectin ligands, and so how cells traffic around the body and are involved in drug resistance. But then this whole area has started to gain, I think, increased focus in the light of immunotherapy. It’s been realized that sialylation, where you have excessive sialic acids on the surface of cells, so a form of glycosylation, can have major effects on how cells interact with each other in terms of the immune response. For example, when you have lots of sialic acid on the surface, it’s literally hard for an immune cell to form an immune synapse with the myeloma cell. But also, these sialic acids can interact almost like a checkpoint, an immune checkpoint ligand, with inhibitory receptors called Siglecs, which are expressed on a variety of immune cells. And you can envisage these Siglecs as being analogous to PD-1, for example. So they’re actually sialic acid binding immunoglobulin-like lectins. And when sialic acid on a tumor cell binds to, for example, an NK cell or a macrophage, it effectively inhibits its function. So in the case of macrophages, they become polarized. They no longer phagocytose properly. NK cells aren’t able to engage properly. They aren’t able to undertake ADCC in the presence of a monoclonal antibody the way they normally would. So given the fact that these are quite important means of activity of daratumumab in patients, we hypothesize that sialylation could potentially have an important effect on the response and outcome of treatment with daratumumab. We first looked at the Cassiopeia study and we were able to get RNA sequencing data from the samples of myeloma cells of patients before going on to study. What we originally noted and we reported this at EHA back in June is that increased expression of this cell transferase ST3-Gal1 was associated with inferior progression-free survival with a hazard ratio, I think that was about 1.65 or something like that. And we went on then to ask the question, well, if it’s associated with inferior PFS, and this is quite significant, is there a possibility that it could impact on MRD? And in the second part of Cassiopeia, patients, after they’ve had their consolidation therapy, they get randomized to have treatment with DARA as maintenance or they just go on to observation. So we had essentially four treatment groups that you could look at patients who had DARA in induction, DARA in maintenance, or DARA induction and just observation, or VTd followed by DARA or VTd followed by VTd. And when we looked at PFS in each individual group, just unfortunately, you know, when you start breaking it down like that, then the numbers aren’t large enough to reach statistical significance. But what we saw was that in the group overall, that there was an impact in the second part of the study on PFS through having high levels of gene expression of ST3-GAL1. And what we realized, in fact, is this just seemed to be limited to the groups that received daratumumab. But more interestingly is then when we look at the patients who are only MRD negative going on to maintenance or observation. So they’re already doing extremely well. That if we look at what happens to those patients two years later, that we found that in patients who had higher levels of, or well, maybe the other way of looking at it is that most patients, 81% of patients were still MRD negative after two years, but within the 19% of patients who had a relapse, who lost their MRD negativity, that high expression of ST3-GAL1 was overrepresented in this group, and this was statistically significant. So there are very few factors that have been described to date that can identify patients who are at increased risk of losing MRD negativity on treatment for multiple myeloma. And so this is potentially a new biomarker that would help us identify patients who are at higher risk. But more so than that, what we went on to show is that in fact, this is potentially actionable because there are ways emerging in the clinic now of actually using drugs that will target excessive sialic acid. So for example, our collaborators in this work, Paleon Pharmaceuticals, have an antibody that’s conjugated with a bisialidase. So it delivers sialidase to the tumor cells and then cleaves off the sialic acids on the surface. And what we found is that in in vitro experiments that when we expose myeloma cells to this bisialidase and then did a co-culture with macrophages in the presence of daratumumab, that the daratumumab was much more effective at inducing antibody-dependent cellular phagocytosis when the myeloma cells had already been desilulated. And in the past, we’ve published that NK cells induce ADCC more effectively following desilulation. And finally, we saw that complement-dependent cytotoxicity could also be enhanced by desilulation. What I didn’t tell you was that in previous work that we’d found that this cell transferase seem to be overexpressed in particularly in patients with high-risk genetic features, including 414 translocation, loss of p53, and 1q amplification, for example. So if it’s highly enriched in those patients who have the worst prognosis, this is a potential mechanism which is contributing to immunovation in those patients and which could potentially be targeted and reversed by using a strategy to remove sialic acids from the surface of tumor cells. So the next steps are to fully validate the role of ST3-GAL1. We feel that this is the gene that’s responsible for generating siglect ligands in multiple myeloma. That’s one sort of first thing to do. The second thing is to validate the findings we have in myeloma cell lines using primary patient samples. Beyond that, I’ve just recently secured a grant to explore how silylation may in fact influence the activity of BCMA bispecific antibodies, because we think that this is certainly a strong hypothesis to believe that this could be something relevant here. There is data out there around silylation influencing T-cell activation and exhaustion. So I think this is a logical next step.

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