Targeting Macrophages in Peritoneal Colorectal Cancer
Hello. I'm David Kerr, professor of cancer medicine from University of Oxford. I'd like to talk today about peritoneal carcinomatosis and some of the underpinning biology that makes this such a dismally prognostic feature of advanced or metastatic colorectal cancer.
There's a fantastic group out of the Academic Medical Center in Amsterdam with Louis Vermeulen and his colleague, Dr Grootjans, the group leaders there, who've done some lovely work in dissecting the immune microenvironment of peritoneal deposits.
They discovered that peritoneal resident macrophages constitute, or create, a very immunosuppressive environment in metastatic peritoneal colorectal cancer. It's difficult to treat. If we look at response rates to conventional chemotherapy, the response rate is one third in the peritoneum compared to that in the liver or lungs. I've often long considered it a pharmacologic sanctuary site. Perhaps it's to do with drug access, drug distribution, and so on.
They've shown, using a mixture of biopsies from patients and in some compelling mouse models, that these resident macrophages play a very important role in suppressing the immune microenvironment.
Of course, they've characterized the macrophages very carefully. We can see the immunosuppressive cytokines, like interleukin-10 and VEGF, so that the whole story is very plausible. Equally as important, in a very relevant mouse model of peritoneal metastasis, they showed that this immunosuppressive phenotype can be reversed by using a CSF1 receptor antagonist.
This is of interest to me because for a long while, we were interested in a very rare tumor type called tenosynovial giant cell tumor, which can be treated very successfully with CSF1 receptor inhibitors.
These drugs exist. They've been approved for the treatment of that very rare macrophage-driven disease, and it looks as if, building on the biology demonstrated by this excellent Amsterdam group, there may be a therapeutic intervention that we could make that's rational and based on depleting these resident macrophages that seem to be the dominant, contributory factor to this rancorous immune microenvironment.
This is another opportunity to build on very plausible biology from an outstanding group with drugs that we may already have available. There's a challenge to those who are using the drugs to treat tenosynovial giant cell tumors. Can we actually bring these into the clinic in some way and consider whether we should give the drugs systemically or even locoregionally by giving them intraperitoneally? I think that would be a really interesting experiment to do.
Have a look at the paper. There are very clever signs, as you would expect, but think about the potential therapeutic implications. You heard it here first.
As always, thanks for listening. I'd be very grateful for any comments or anything you might like to add to this. For the time being, as always, Medscapers, over and out.
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