Highly mutated cancers respond better to immune therapy | Hacker News Reader

Highly mutated cancers respond better to immune therapy

nature.com

26 pointspseudolus6 comments

That’s not the important conclusion of the primary article. Highly mutated cancers of certain types respond better to checkpoint inhibition and so forth. Melanoma, lung adeno, colorectal with MMR defects, for example. Others (glioma, high-grade serous ovarian, germ cell for example) don’t seem to get “hot” immunologically in proportion to their mutation burdens. (And there are other tumors, serous ovarian hypercalcemic for example, that have a vanishingly low mutational burden and respond to checkpoint inhibitors anyways).

The initial results suggested that more mutations == more immune response. That’s clearly not universal enough to rely upon clinically, although in some tumor types it’s suitably reliable to stratify clinical trials. In other tumor types, it looks like we are stuck with trial and error to find good enough biomarkers for response, as with most drugs.

So while TMB can be useful, it has limitations, and this study (the primary results, published in Nature Genetics, a related but different journal) helped clarify where those limitations are. The news & views piece just has pull quotes.

I think there were some trials with negative results trying to link just TMB to immune response or outcome. It's really about problems with MMR genes.

Not only, and not always. HGSOC-hypercalcemic is a particularly notable exception. The idea that it’s always MMR came from Lynch syndrome, but that doesn’t seem to be universal.

Immunity is complicated, you heard it here first...

Makes sense, the immune system is for detecting things that aren’t “you” and killing them, so the more mutated it is the less you it is — the easier it is to kill. Intuitively, anyways.

I wonder if this is what spontaneous remissions are all about: the cancer mutates to the point that the immune system picks it up and knocks it out?

The headline is a bit misleading and if you look at the landscape of cancer immunotherapy research you will see this generalization does not hold at all i.e. tumor mutational burden is not necessarily a good predictor of response in all types of tumors. See apathy's response above. W.r.t spontaneous remission, there have been a few lines of research that would seem to lend credence to your hypothesis (e.g. - see http://www.fevertherapy.eu/) but it has never been studies systematically enough to draw any conclusions one way or the other.

This makes sense. Barely mutated cancers are harder to distinguish from cells with benign mutations.

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