ESMO Immuno-Oncology 2025 | Management of liver metastases in solid microsatellite stable cancers

Well, so the natural version of this presentation is, of course, to summarize the developments in recent years and where we’re at right now and what the challenges are. So in essence, what we see as a continuing problem is that in microsatellite-stable GI cancers especially, but also in melanoma, liver metastases are an enormous challenge for immunotherapies of all sorts and kinds so the overarching topic is that the liver and the liver microenvironment present an enormous hurdle for immunotherapies to be successful and digging deeper into this there have been multiple efforts in trying to tackle this problem and attacking sort of the liver environment specifically but but looking at this picture it becomes clear that this is something that is not only related to the liver but also the abdominal cavity and especially the peritoneal microenvironment they’re not really really amenable to immunotherapy whatsoever. And they’re sort of an ecosystem that is intrinsically resistant to our current standard approaches in immunotherapy. So what this presentation will encompass is summarizing the state of the art of treatment, which is basically showing that in MSS GI cancer specifically, the immunotherapy is failing. It’s not working, especially in the setting of liver metastases. So for colorectal cancer, the picture that has emerged is that even if one tries to circumvent this problem by simply selecting patients that are free of obvious liver metastases and have an uncommon, let’s say, setup with lesions in the lungs, for example, the success rate of immunotherapy still is not really very, let’s say, promising to say the least. So this is still a remaining problem also there. It’s not just the liver, but it shows that certainly the liver is the biggest hurdle, but it’s not clearly the only hurdle that we have to face in these microsatellite stable tumors. So this being said, the evidence in terms of trying to ramp up efforts, especially from clinical trials, shows that multiple avenues have been tried. Combination therapies and encompassing tyrosine kinase inhibitor combos with checkpoint inhibition and whatnot are not successful. And they have been large trials, even two really multi-institutional efforts that didn’t come up with a conclusive picture that would indicate that there’s a specific regimen that is successful. This is, of course, also then for asking the question what is the right combination of immunotherapies so maybe there are other signaling pathways that are more relevant and we’re simply missing out on these. There have been also efforts along those lines trying to play around with what kind of checkpoint inhibition might be of interest here and how this could leverage the problems of resistance. And so far, again, there has been no progress. These, let’s say, results that we see are at best limited. And for the majority of attempts, they’re simply not successful. And the obvious choice then would be to say, okay, if we can figure out another type of intervention, for example, cellular therapy-based approaches that would circumvent this problem by sort of leaving out these checkpoints, leaving out classical tyrosine kinase inhibitors, maybe this would be an option, but what we see there is that, in fact, there’s also only limited efficacy in the liver as well. There are some reports on newer developments with viral therapy where we see that there can be also a limited effect, but this is only in very small cohorts and also remains to be seen whether this will break the barrier or not. And there’s currently, not to my knowledge at least, a cross-entity approach specifically targeting with the immunological pathways or modulation of these pathways to deliver metastases. So that’s the current situation as it is and the open challenge that’s out there.

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