4 ms·
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 no
by astazangasta 10y ago
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 great at acquiring novel mutations to become resistance to therapy, losing a mutation is even easier. All you have to do is ditch one arm of a chromosome, revert the mutation, or otherwise eliminate the novel mutation, and your tumor cell is now resistant to this therapy.
Add to this the fact that we are basically shit at predicting which mutant proteins will produce neoantigens and you have a recipe for total failure, even in concept.
- return0 10y agoHow long will this process take? Is it enough to create a new therapy to target the mutated cancer?
- astazangasta 10y agoPeople 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.
- return0 10y agoBut what if the antigens are vital for the tumor ? What mutation are you referring to? Presumably the immune system will kill the cancerous cells ( shedding the mutation as well).
- darawk 10y agoCould 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.
- danarlow 10y agoYes, this reasoning is correct. Same principle applies to combination therapies for HIV, malaria, etc., where you're at risk of developing a resistant strain within the patient. Not sure why it isn't more common among cancer therapies. Maybe not enough unique targets?
- robbiep 10y agoNot enough unique drugs, difficulty determining mutations/susceptibility of tumour to drug, high side effect profile of drugs used in isolation and higher still in combination
- themartorana 10y agoCan you turn off a mutation's ability to adapt and mutate?
- robbiep 10y agoIt 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
- dnautics 10y agohey - 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 laden) therapies? I was always a bit aware of the pernicious "maintenance drug" status of gleevec, but presumably if you combine it with an orthogonal therapy you could get higher coverage and better statistical odds of sending the patient into remission.
- robbiep 10y agoImatinib 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
- dnautics 10y agoah... so standard chemo/rad isn't used because the immune response to clear out the senecent bastards will be compromised.
- vibrio 10y agoAgreed 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.
- melling 10y agoI assume that you haven't heard that immunotherapy is the new big thing in cancer research? It's how they cured former President Carter: http://www.forbes.com/sites/arleneweintraub/2015/08/21/jimmy-carter-melanoma-and-the-promise-of-immunotherapy-in-the-elderly/ http://www.forbes.com/sites/arleneweintraub/2015/08/21/jimmy...
- astazangasta 10y agoI do cancer research at UCSF on an immunotherapy project...
- unimpressive 10y agoI'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 negatives with downvotes.
- megalodon 10y agoAgreed, people seem to be downvoting because they hope he/she's wrong rather than to post a reply explaining their reasoning. I see nothing wrong with the root comment and just upvoted it to give it more attention.
- return0 10y agoGive it an hour or so. the hivemind is usually strong in the beginning.
- dghughes 10y agoWell, we all know that now but not for the first comment.
- baldfat 10y agoShould be Down votes = troll or argumentative or factually wrong Actually Down votes = I disagree I have quit HN many times over that but there isn't anything that can replace HN right now.
- chrisdbaldwin 10y ago"Add to this the fact that we are basically shit at predicting which mutant proteins will produce neoantigens and you have a recipe for total failure, even in concept." Do you think if we had more data surrounding those mutant proteins we could start predicting better?
- refurb 10y agoWhat about the CAR-T therapy that has work pretty well against blood cancers (ALL and CLL if I remember correctly)? Seems there were a handful of remissions in patients who had failed everything else. What makes this approach so destine to fail? It's an honest question as I'm not as familiar with the details.
- reasonattlm 10y agoCAR-T is a step in the right direction for the cancer research establishment, not because it solves the problem noted by the parent comment, but because it offers the prospect of greatly reducing the cost of targeting many different types of cancer. It is very much the luck of the draw going cancer by cancer as to whether you can pick a target that is more or less likely to be evolved around by the cancer. Leukemias were a lucky hit, but that may or may not hold up for other targets and other cancers as they are put forward.
- jonknee 10y agoAlmost all trials fail, but it's interesting that CRISPR is getting the nod. It has so many uses that if it doesn't work in this specific cancer study it doesn't really matter.
- reasonattlm 10y agoWhich is a good reason to back things like telomere lengthening interdiction. That would work on all cancers, and cancers can't evolve around that dramatic a hurdle, so far as we know. It is a very fundamental set of machinery, and all cancers have to lengthen telomeres in order to stay ahead of the limits to replication. Some groups are working on blocking the action of telomerase, but to make a viable treatment ALT (alternative lengthening of telomeres) will have to be blocked too, since researchers have already seen telomerase-abusing cancers turn into ALT-abusing cancers.
- deleted 10y ago[deleted]
- maxander 10y agoDepends 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 intervention in line with most standard cancer treatments. As a total cure for cancer it will "fail," but then, so have all the breakthrough cancer treatments that have collectively shattered the mortality rates of cancer patients. (You mention you're involved in cancer research, so you presumably know all this already- I'm wondering if there's a more nuanced reason for this pessimism.) The best theory I've heard so far as to how we'll "cure cancer" altogether is that we'll simply develop a big enough armory of anticancer treatments that no individual cancer case could evolve fast enough to beat them all. Unlike bacteria or viruses, cancers evolve on their own and when they're done their evolutionary innovations die with them. Our technology lives on, though, so we can hope to eventually just totally outclass their capabilities. If CRISPR gives us another source of these partial treatments, we're just that much closer to that level.
- astazangasta 10y agoThis 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.
- danieltillett 10y agoI was under the impression that the major reason for the failure of current immunotherapy treatments is due to non-response, not excessive autoimmunity.
- jacquesm 10y agoFor 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.
- danieltillett 10y agoI agree that this trial is almost certain to fail, but as I am sure you know the resistance mutatants are normally preexisting in the patient before treatment and the treatment just selects for the resistant mutants. I think one of our bigger problems with fighting cancer is we only trial new treatments in people on deaths door who have failed everything else. Treatments that would help someone newly diagnosed (the treatments we really want) are just not possible to bring to market.
- marcosdumay 10y agoWell, if it only fails to cause autoimmune diseases as a collateral effect, it'll be already a huge win for CRISPR techniques in the future.
- ihodes 10y agoMy understanding is that this trial is just 1. adoptive CAR T cell transfer (which has been shown to work with varying degrees of success) 2. PD-1 is CRISPR'd out (to combat exhaustion) 3. The TCR is CRISPR'd out (to increase specificity) CAR Ts have certainly had some success; my concern with this trial would be more autoimmune problems, not that it would fail hard. Is there something else about this trial that would make it unsuccessful?