3 ms·

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 c

by dm319 4y ago

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.

suslik 4y ago
> 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?
- dm319 4y ago
  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).
evandijk70 4y ago
Different treatment, but tumors receptive to EGFR-treatment almost always develop secondary resistance to treatment by additional mutations. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367712/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367712/
- dm319 4y ago
  Yes good point.
ramraj07 4y ago
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.
- dm319 4y ago
  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.
bglazer 4y ago
KRAS does this. Doesn’t necessarily invalidate your point, but it is interesting. https://www.sciencedirect.com/science/article/pii/S1556086421021328 https://www.sciencedirect.com/science/article/pii/S155608642...

by dm319 4y ago

suslik 4y ago

> 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?

dm319 4y ago
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).

evandijk70 4y ago

Different treatment, but tumors receptive to EGFR-treatment almost always develop secondary resistance to treatment by additional mutations. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367712/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367712/

dm319 4y ago
Yes good point.

ramraj07 4y ago

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.

dm319 4y ago
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.

bglazer 4y ago

KRAS does this. Doesn’t necessarily invalidate your point, but it is interesting. https://www.sciencedirect.com/science/article/pii/S1556086421021328 https://www.sciencedirect.com/science/article/pii/S155608642...