Crispr Wins Key Approval to Fight Cancer in Human Trials • Hacker News Board

Re: Crispr Wins Key Approval to Fight Cancer in Human Trials

#41

Post by robbiep » Thu, Jun 23, 2016, 8:35 PM UTC

themartorana wrote: post #34

darawk wrote: post #17

Earlier quoted context omitted.

Could you simultaneously target multiple mutations to reduce the risk of this? Similarly to using a cocktail of antibiotics to prevent the development of resistance. i.e. the probability of shedding a single mutation is 1/x, but the probability of shedding two in the same organism is (1/x)^2, so targeting more mutations make it exponentially harder for the organism to adapt.

Can you turn off a mutation's ability to adapt and mutate?

It would be called killing the tumour. The only way to destroy mutation is to destroy replication. We don't know how to increase the fidelity of DNA replication, and cancer cells have their error correct mechanisms all destroyed

Re: Crispr Wins Key Approval to Fight Cancer in Human Trials

#42

Post by robbiep » Thu, Jun 23, 2016, 8:40 PM UTC

dnautics wrote: post #20

astazangasta wrote: post #7

Earlier quoted context omitted.

People develop resistance to TKIs (tyrosine kinase inhibitors, the previous mode of therapy) within months; you could keep chasing the dragon, but the tumor is just going to keep doing the same thing, shedding whatever mutation you target. In this case you're not even targeting mutations that the tumor relies on (as you are with a TKI), so there's absolutely no fitness cost to the tumor to evade.

hey - just want clarification. I thought TKIs like gleevec give an asymptomatic period of years - do you mean by "develop resistance" the initial seed population of cells that are resistant emerge from a (presumably clonal or near-clonal) pool within months? Second: Do you know if clinically, agents like gleevec are primarily used as standalone or in conjunction with more aggressive (and, unfortunately, side-effect l…

Imatinib and other TKIs provide a range of effectiveness, from weeks/months to years. Nothing is forever (although the CD1 Ligands like ipilimumab etc show promise).

Mostly, the TKIs spread the Kaplan-Meyer curve out/lengthen it, but because it is still relying on the immune system to kill the cells (mostly) essentially TKIs are providing cellular senescence rather than cellular death. The bcr/abl mutation that imatinib targets is a cellular replication pathway, not s cell death pathway

Re: Crispr Wins Key Approval to Fight Cancer in Human Trials

#43

Post by vibrio » Thu, Jun 23, 2016, 8:42 PM UTC

unimpressive wrote: post #11

astazangasta wrote: post #9

Earlier quoted context omitted.

I do cancer research at UCSF on an immunotherapy project...

I'm not one to usually complain about downvotes, but this is ridiculous. The HN hivemind at its most absurd. This person is literally working in the research sector involved, giving their opinion (it's not a nice opinion, but it is presumably informed), and getting downvoted because the HN crowd doesn't like it. EDIT: At the time I wrote this comment the parent comment and the root comment were both far into the nega…

I agree with you that the down voting is silly, as s/he makes some good points, but suspect the down voting was in reaction to the tone of the comment. If one was holding a lab meeting and a comment arose in that tone, one could image other lab member getting defensive. tl;dr The comment would have been more effective without the passion of fail'hard' and other language.

Re: Crispr Wins Key Approval to Fight Cancer in Human Trials

#44

Post by JoshTriplett » Thu, Jun 23, 2016, 9:00 PM UTC

ceejayoz wrote: post #30

ddorian43 wrote: post #26

Earlier quoted context omitted.

And are you doing something about it (donating/investing/working/etc) ?

Chances are anyone in a developed-world democracy is investing/donating via their tax dollars.

Not very effectively or with the focus you might want, though.

Re: Crispr Wins Key Approval to Fight Cancer in Human Trials

#45

Post by astazangasta » Thu, Jun 23, 2016, 9:00 PM UTC

maxander wrote: post #35

astazangasta wrote: post #4

I'm calling it here, this trial will fail hard. The basic idea is this: the cancer has a number of mutations that produce novel antigens that don't exist in normal cells. If we can train T-cells to recognize these, they can attack the tumor with great specificity and kill those cells. The problem is, all the tumor has to do to evade this targeting is shed the problematic mutation, which is easily done - tumors are gr…

Depends on what you mean by "fail hard," I suspect. Sure, cancer cells can gain or lose mutations, but if we target a mutation important for cancer development only a fraction of the target cancer will survive the treatment. We might achieve nice-to-have results like reduction in tumor size and increased patient life expectancy, or a "cure" in lucky patients with less agile cancers, which would put this radical new i…

This method is not targeting mutations important for cancer, this is targeting "passenger" somatic mutations. You can't use this mechanism to target important mutations because only a minority of patients are going to be able to present an oncogenic mutation (e.g. BRAF V600E) as an antigen (because of differing HLA types). In those rare cases perhaps this therapy might succeed, although the tumor probably still has ways of evading (downregulating the offending HLA for example).

As for the "kitchen sink" approach, so far none of the methods we've developed are free from side effects. Cancer patients are often on the edge of death; each successive therapy will probably do more damage to them. As it is most people fail on current immunotherapies because of autoimmune reactions. So relentless application of therapies is not necessarily going to work, though of course having more weapons in our arsenal is great.

Re: Crispr Wins Key Approval to Fight Cancer in Human Trials

#46

Post by JoshTriplett » Thu, Jun 23, 2016, 9:02 PM UTC

ddorian43 wrote: post #26

zymhan wrote: post #2

I hope that by the time I'm succumbing to the effects of aging, we'll have techniques with tools like CRISPR to make it easier.

And are you doing something about it (donating/investing/working/etc) ?

I'm sad to see this downvoted. It's reasonable to try to turn expressions of support on a forum into action.

For anyone who wants to support research into ending aging, age-related degeneration, and related diseases, I'd recommend supporting SENS (http://www.sens.org/).

Re: Crispr Wins Key Approval to Fight Cancer in Human Trials

#47

Post by [deleted] » Thu, Jun 23, 2016, 9:04 PM UTC

maxander wrote: post #35

astazangasta wrote: post #4

I'm calling it here, this trial will fail hard. The basic idea is this: the cancer has a number of mutations that produce novel antigens that don't exist in normal cells. If we can train T-cells to recognize these, they can attack the tumor with great specificity and kill those cells. The problem is, all the tumor has to do to evade this targeting is shed the problematic mutation, which is easily done - tumors are gr…

Depends on what you mean by "fail hard," I suspect. Sure, cancer cells can gain or lose mutations, but if we target a mutation important for cancer development only a fraction of the target cancer will survive the treatment. We might achieve nice-to-have results like reduction in tumor size and increased patient life expectancy, or a "cure" in lucky patients with less agile cancers, which would put this radical new i…

[deleted]

Re: Crispr Wins Key Approval to Fight Cancer in Human Trials

#48

Post by jacquesm » Thu, Jun 23, 2016, 9:07 PM UTC

astazangasta wrote: post #4

I'm calling it here, this trial will fail hard. The basic idea is this: the cancer has a number of mutations that produce novel antigens that don't exist in normal cells. If we can train T-cells to recognize these, they can attack the tumor with great specificity and kill those cells. The problem is, all the tumor has to do to evade this targeting is shed the problematic mutation, which is easily done - tumors are gr…

For the downvoters: the fact that the parent does not think it will work says nothing about whether or not he would hope that it would work, it's just that he's a bit more informed than most here.

Re: Crispr Wins Key Approval to Fight Cancer in Human Trials

#49

Post by ceejayoz » Thu, Jun 23, 2016, 9:09 PM UTC

JoshTriplett wrote: post #44

ceejayoz wrote: post #30

Earlier quoted context omitted.

Chances are anyone in a developed-world democracy is investing/donating via their tax dollars.

Not very effectively or with the focus you might want, though.

I tend to believe the NIH is better at administrating grants than I am.

Re: Crispr Wins Key Approval to Fight Cancer in Human Trials

#50

Post by vibrio » Thu, Jun 23, 2016, 9:11 PM UTC

astazangasta wrote: post #7

return0 wrote: post #5

Earlier quoted context omitted.

How long will this process take? Is it enough to create a new therapy to target the mutated cancer?

People develop resistance to TKIs (tyrosine kinase inhibitors, the previous mode of therapy) within months; you could keep chasing the dragon, but the tumor is just going to keep doing the same thing, shedding whatever mutation you target. In this case you're not even targeting mutations that the tumor relies on (as you are with a TKI), so there's absolutely no fitness cost to the tumor to evade.

Agreed that for most tumor types targeting single antigens is a fool's errand, but the claim that "here is absolutely no fitness cost" for mutational evasion seem like is an overstatement. This is clearly false when using bacterial resistance to antibiotics as a more tractable proxy.