Immuno-oncology in Colorectal Cancer: A Sneak Peek

David J. Kerr, CBE, MD, DSc, FRCP, FMedSci


March 27, 2017

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Hello. I am David Kerr, professor of cancer medicine from the University of Oxford in Oxford, England. Let us call this "Old Kerr's Almanac."

The year 2016 was dominated by immuno-oncology. The year 2017 will also be dominated by immuno-oncology; I have no doubt about that. Let us consider what this may mean for colorectal cancerology.

Some of the lovely work in this area is looking at microsatellite unstable disease and how that highly mutated poly-antigenic tumor does seem to comprise a subset of patients with advanced colorectal cancer who may respond to immune checkpoint inhibitors. David Church and colleagues[1] have published some very nice additional work looking at mutations in DNA polymerase-Ɛ, where another 1% or 2% of patients with colorectal cancer have an even higher mutational burden than with microsatellite instability. We would hypothesize that these patients also would be candidates for novel immunotherapy.

I will be interested in seeing some combination work coming out: not just immune checkpoint inhibitor plus immune checkpoint inhibitor—which would be pretty toxic, terribly expensive, with a definite but marginal benefit seen so far—but some rather mechanistically novel treatments. We are terribly interested in the concept of combining histone deacetylase (HDAC) inhibitors—modulators of epigenesis—with immune checkpoint inhibitors. We have some data from my colleague, Nick La Thangue,[2] suggesting that HDAC inhibitors can switch on major histocompatibility complex (MHC) I and MHC II and may have effects on infiltrating Treg cells. We may be able to light up the tumor, in a way, increase its immunogenicity, and reduce the degree of immunoediting by pretreating with a clever sequence combination of HDAC inhibitors and immune checkpoint inhibitors.

I believe that it may also be possible within the wider group of colorectal cancers to define a proinflammatory subset that may go beyond the burden of microsatellite instability in polymutations, a subset of inflammatory tumors that may be candidates for treatment with immune checkpoint inhibitors.

I hope to imagine that we will see an increased parsing in a subselection of colorectal cancers, to see if we can bring immune checkpoint inhibitors to the field of play. Thank you for listening. Over and out.


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