I haven't seen evidence of cancers re-mutating mutations. They tend to develop new mutations (as in the clonal evolution hypothesis), and they can completely change their cell surface expression. But I suspect that they are unlikely to mutate an already mutated gene.
I guess for the treatment to be most effective you need to target some of the earlier mutations, rather than a small clone.
From my perspective, and not having read the paper, I thought the technology to predict what TCR would bind a particular peptide on a particular MHC-1 was not there yet.
Cancers have higher mutation rates and also constantly rearrange their genome including deletions. Given that they’re looking for Novel epitopes it goes to reason these are not high copy number hence deletions can also remove them fully. It’ll be hard for me to believe that a mutagenic cancer (which is a given here since you’re looking to treat cancers with actual mutations) will not eventually gain resistance to this therapy.
Yes you are right, I should have said that re-mutation of mutations happen far less often than accumulation of additional mutations.
Novel epitopes should be high copy number - and driver mutations will be present in 80-100% of the cancer cells. It depends how many cancer cells you get in your biopsy that you sequence I guess.
It is easier for a cancer cell to mutate or remove a cell surface protein than to mutate the same mutation targeted, but you are right - that can happen and I'm sure will be a form of treatment resistance for these types of treatment in the future.
> But I suspect that they are unlikely to mutate an already mutated gene
Could you elaborate? I'd like to understand what you mean, as I don't work on onc. Aren't recurring mutations in response to treatment in f.e EGFR is the reason we keep developing multiple generations of small molecule therapies for it?
Yes, I didn't mean impossible, I just mean compared to accumulating new mutations elsewhere, and compared to downregulating surface proteins (which can be the issue in CAR-T).
I guess for the treatment to be most effective you need to target some of the earlier mutations, rather than a small clone.
From my perspective, and not having read the paper, I thought the technology to predict what TCR would bind a particular peptide on a particular MHC-1 was not there yet.