Identifying myeloid-driven biologies
Dr Brian Ruffell - Moffitt Cancer Center, Tampa, USA
Probably the most well developed target right now is focussing on macrophages and in particular a receptor that they express called colony stimulating factor 1, for short it’s CSF1 receptor. So there are multiple compounds, either in preclinical or clinical development and they’re showing they’re good at depleting macrophages, at least in the trials, we’re still waiting to see whether they show efficacy either alone or in combination.
I tried to break it down for us, since it was an education session, into three main concepts of studying myeloid cells and it was really form, function and context were the three main fields. One was to understand what myeloid cell you’re looking at which could be quite hard because they’re very plastic cells and they take on new phenotypes depending on what tissue they’re in and what context they’re experiencing. That was the second issue was the context of those cells, whether you’re talking about them in colon cancer or lung cancer or breast cancer their phenotype and their function will be unique. Then you have to deal with the fact that you’re going to add in therapeutic modalities on top of that and that will further change what they’re doing. So if they’re responding to paclitaxel chemotherapy in general versus radiation therapy you may see very different dynamics on the role of those populations.
What did you find?
We certainly expect that as a certain patient was undergoing different rounds of chemotherapy or radiation therapy or any kind of new checkpoint inhibitors that the phenotype of those cells will change and certainly their function will change. We’re really just now starting to dissect that out but at least in preclinical models they’ve found that if you combine targeting of macrophages with the aforementioned CSF1 receptor pathways you can enhance response to checkpoint blockade, chemotherapy, radiation therapy. But the role of the cells in each of those circumstances will be unique.
Did you receive any feedback regarding checkpoint blockade?
It was not the focus of our session in particular but that is the way that everyone is looking and so whenever we’re studying any other molecule now it’s going to be in the context of does this relate to checkpoint blockade, in particular PD-1 and PD-L1 therapy? So there have been two papers now showing in preclinical that targeting these pathways works for checkpoint blockade. There are a number of stories in development, some of them that we saw here at AACR showing that you can see combination. There was a talk the other day showing you see combination in mesothelioma, for example, within the lung and these kinds of stories are coming to the forefront right now.
Are there any ongoing CSF-1 pathway trials?
There are multiple trials ongoing with various drugs in various types of cancers right now. Because of how novel it was they’re still waiting on results from that. The safety profiles look promising and so they’re moving forward with those but efficacy, none of that data is available yet.
What’s next for the CSF-1 pathway?
We see it usually in combination with other therapies. So, with one exception, they’re fairly ubiquitous, it has been shown that we have to combine these targets with other therapeutic modalities to see efficacy and that’s, of course, in preclinical models. So with all that in mind we realise it’s going to be one part of a package of therapies that are administered to patients.
What kind of combinations?
Right now it’s being tried with chemotherapy, it’s being tried in prostate cancer with androgen deprivation. I’m not sure whether it’s tried with radiation therapy or not and checkpoint blockade there will be a combination either now or shortly from now for sure.
What is your take home message?
We’re making substantial progress now in really trying to break down what the role of those cells are and understanding that we have to use multiple combinations to target those with other therapies. The field was held back by technology to some degree, as those have advanced we’ve been able to dissect the populations out and understand their function at a much greater detail. That has helped us to figure out what’s going on. The future questions will be what’s the best context to use them in and things like the temporal administration – should we be treating before therapy, in the middle of therapy or after therapy long term? Which of those would be the best way to go forward? That’s the question when we’re talking myeloid cells and macrophages or any other therapeutic context; that theme has come up repeatedly in the context of checkpoint blockade as well.