This is certainly an interesting and theoretically promising method, that, if it works, should make it fairly easy to develop specific personalized "vaccines" for each person's cancer.
For background, dendritic cells are a type of antigen-presenting cells, which means their job is to pick up proteins, break them up into small pieces (antigens), and then show those pieces to T-cells, whereupon the T-cells can either say "looks like a self antigen, everything's fine" or say "that looks like a foreign antigen, raise the alarm!" and then initiate a specific immune response against that antigen.
The basic concept here is that if you have a specific protein that you want to raise an immune response against, you can do so by tricking dendritic cells into producing copies of that protein, which will then get presented along with all the other antigens for inspection by T-cells. You can pull off this trick by feeding RNA that encodes the target protein to the dendritic cells, and as a bonus, the fact that there's free RNA floating around triggers anti-viral defenses, which causes the T-cells to be extra suspicious of the antigens they're inspecting (i.e. it lowers their threshold for raising an immune response). But injecting RNA directly into your spleen isn't exactly practical, so instead they found that attaching the negatively charged RNA to some positively charged lipids in a specific ratio (which results in a specific ratio of charge to mass) causes them to localize to the spleen and then get taken up, translated, and presented by dendritic cells when injected intravenously.
So, put it all together, and the workflow for treating cancer looks something like this:
1. Find a protein produced by the cancer cells that is either sufficiently different from the same protein in normal cells (due to mutation) or not produced in normal cells.
2. Construct an RNA transcript that will produce that protein when translated.
3. Attach that RNA transcript to the liposomes in the appropriate ratio, and inject it into your bloodstream.
4. Let the immune system do its thing.
5. Repeat as necessary to keep the immune response active until it's killed all the cancer.
Obviously step 1 is still the hard part, and the paper chose as a proof of concept two example cancers for which this step was already done. But finding a viable cancer-specific antigen is certainly orders of magnitude easier than determining the mechanism of a cancer and then developing a treatment specific to that mechanism.
Yes, it certainly seems elegant, but with biology (and science in general), you always have to keep in mind that the (apparent) elegance of an approach is predicated on the assumption that we have an accurate understanding of how the system in question works, which frequently turns out not to be the case.
Thanks for the great summary. But I'm guessing previous immunotherapy based treatments are also based on stimulating T-cells to fight cancer cells. Any idea why they didn't work? This method only makes it easy to stimulate T-cells, but what about mutations in cancer.
The job of the immune system is to distinguish self from non-self and to seek and destroy any non-self that it discovers. If you want to get the immune system to fight something, you need to get it to recognize that something as non-self, preferably without also forcing it to recognize your own healthy cells as non-self (because then you'd have autoimmune disease). Cancer is an especially difficult case for the immune system because for the most part, cancer cells are your own cells with just a few mutations[1]. The vast majority of proteins produced by cancer cells are the same proteins that your healthy cells produce. They may be produced in different proportions, regulated differently, etc., but they are the same proteins. Even the proteins that mutated could have only a single amino acid change relative to the original. So the difference between healthy cells and cancer cells at a molecular level is much more subtle than the difference between your cells and bacterial cells, for example. It's not impossible for your immune system to identify cancer cells, but it's obviously not guaranteed either. (There's a nigh-untestable theory that a majority of cancers are actually detected and destroyed by the immune system long before they become symptomatic, so the ones we see are just the ones that managed to evade the immune system in their early stages.)
As I've mentioned above, this paper skips the hard part of finding a suitable protein target by picking two proof-of-concept cancer models for which a suitable "non-self" target is already known.
[1] Actually many mutations, but few that affect protein sequences, which are what T-cells mainly look at.
Paywall: I read this as an ability to help in immunotherapy which works like a vaccine. I really am interested in what types of cancer this works with the strongest effect. They list soft tumors in Lungs.
The bellow citation seems to show that these are something that could work on all cancer types and is cheap. These are exciting times.
Now it will be another 5 years till we see this even in a trial for children? (Son and sister died of cancer and my daughter's 10 year old friend (same cancer as my sister) is in immunotherapy trial which we are praying for a miracle for her reoccurring brain cancer.
> RNA-LPX vaccines are fast and inexpensive to produce, and virtually any tumour antigen can be encoded by RNA.
It's very exciting, but as these therapies become more successful, we're going to have to tackle the adverse reactions both acute, and chronic. Granted, you're surviving cancer so that's not the primary concern, but it will be a concern.
Well that is the Number One Reason why they are going immuntheraphy the side effects are minor compared to Chemo and Radiation. This is your own body fighting the cancer.
I don't think "Minor" is accurate. A good friend just went through this to beat a strange form of metastatic blood cancer, and he was in the ICU for a week as a direct result. (and essentially comatose) It was worth it, since he went from, "Plan your death" to, "Full remission!". Still, he was strong going in, a lot of people would have died.
Right now, there's still a lot of art to the balance between having your immune system fight hard enough to kill the cancer, without setting off a cytokine storm that kills you. There's also the issue of longer term autoimmune complications, which I suspect will turn out to be the "secondary cancers" of the immunotherapy world.
There's nothing to say that leveraging your own immune system will necessarily reduce the frequency or severity of side effects relative to current therapies. Your immune system is quite capable of killing just about any cell in your body, foreign or not. The multitude of different autoimmune diseases are clear evidence of that fact.
Out of curiosity, what brain cancer does she have? I had a Grade II astrocytoma in 2013, came back in Sept 2015 as Grade III. Currently undergoing chemo and feeling fine (25 years old).
Assuming this kind of therapy is effective in humans, the rate-limiting step is identifying a protein in the cancer that is either not produced in normal cells or sufficiently mutated relative to the same protein in normal cells, such that the immune system targeting that protein will only kill cancer cells. Otherwise you'd just induce autoimmune disease.
Are you asking how to identify such a target protein? Well, you could sequence cancer peptides using mass spectrometry, or sequence the cancer cells' genome, and look for proteins that are sufficiently mutated relative to the wild type copy. However, we already have pretty good knowledge of which genes tend to be mutated most often in cancer cells, so you could do targeted sequencing on those genes first to look for low-hanging fruit. In general, it's still a hard problem, though.
Really it is pretty random as to what cancer research and development gets more or less attention from the media and public. Merit has little to do with it. You should assume that any given article like this is representative of many similar ones that passed by without comment.
The most important thing for any approach aspiring to be widespread in the next generation of cancer research is how costly it is to adapt the platform to any specific cancer. The only way to make real inroads in control of cancer is to crush down the cost of addressing different cancers, making it a small project rather than a whole new research initiative each time around.
>The only way to make real inroads in control of cancer is to crush down the cost of addressing different cancers, making it a small project rather than a whole new research initiative each time around.
Agreed. And while this study's methods wouldn't be cheap per se, RNA-based methods combined with whole genome sequencing of tumors are much more cost (and time) efficient methods than approaches that require antibodies or chimeric proteins. I believe that these methods, in combination with immunotherapy, are the best candidates for future cancer therapy.
Immunotherapy is indeed the most promising approach to cancer therapy so I'm optimistic, but the odds of success here are 1-in-20 if this is an average study, or perhaps 1-in-5 at best.
You certainly have chosen the right user name, but it is a logical error to use the success rate of all cancer trials to calculate the chance of success of this immunotherapy trial.
Stupid/insensitive question: what if cancer were a species "feature" earned through evolution that helps reap people who made it through their reproductive years without accident or disease but are now more hindrance than help to the species?
Because evolution doesn't work on a species level, it works on a gene level. Genes that help propagate themselves spread more. A cancer causing gene would almost certainly be selected against, vs a gene that caused you to live longer and have more children - and spread more copies of itself.
The reason people die is not because it's better for evolution. It's because evolution simply doesn't care about maximizing life expectancy. Most organisms die long before they get cancer, so the fitness of a gene that prevents cancer is pretty small.
> Because evolution doesn't work on a species level, it works on a gene level. Genes that help propagate themselves spread more.
I don't think that's necessarily the case. If my descendants were able to reproduce more because of my gene that reaped me before I was a drain on their resources, that gene could be inherited by them.
IIRC I vaguely recall something about male homosexuality being correlated with female siblings' increased offspring count. It's a stretch to say that they'd be caused by the same gene but it would be an interesting phenomenon which might be a net benefit to the species.
I take issue with your first statement- evolution certainly works at the species level (in the sense that population genetics is a thing). It does appear there is a population fitness that is selected for when two desirable phenotypes can't be accomodated in a single individual.
Also, "Most organisms die long before they get cancer, so the fitness of a gene that prevents cancer is pretty small." ignores the fact that there are genes preventing cancer (tumor suppressors), and those genes are under active selection.
>evolution certainly works at the species level (in the sense that population genetics is a thing).
That's not at the species level. That's, at the very best, at the level of a very small group. And most of those theories have generally been discredited - it only works if the beneficial effect on the group is sufficiently large, see http://lesswrong.com/lw/kw/the_tragedy_of_group_selectionism...
>there are genes preventing cancer (tumor suppressors), and those genes are under active selection.
That doesn't contradict what I said. Those genes work well enough to prevent cancer in young organisms, but they are clearly not enough to stop all cancer.
Why hasn't evolution evolved away all cancer? Because even if there was a gene that could decrease cancer risk by an additional 1%, it wouldn't actually increase fitness that much. A 1% decrease in risk is small on it's own, and then it only affects the 1% of organisms that haven't already died of other things. Preventing cancer is just not in evolution's priorities - at least not past a certain point.
I concede I was probably inaccurate in my statement about evolution and the species level; note, however, that I disagree with people who believe that the gene is the unit of evolutionary selection (I would refine it to say "functional region" rather than gene because I believe that mutations in enhancers and other transcriptional activators play a bigger role in evolution that mainstream science).
On to your second reply:
I basically agree. We're mostly arguing about where that certain point is. Problem is: cancer is a disease that is closely tied to many necessary functional parts of multicellular organisms.
In a sense cancer is what gets people who weren't got by something more acute earlier, and probably evolution is addressing the more acute issues with a higher priority.
The term "tumor suppressor" doesn't necessarily mean that the gene exists for the sole purpose of preventing cancer. It just means that the protein's normal function happens to prevent cells from becoming cancerous. Many DNA-repair proteins fall into this category, for example, simply because repairing errors in a cell's DNA reduces the probability of that cell accumulating cancer-causing mutations. And yet, DNA-repair proteins pre-date the evolution of multicellular organisms, so they cannot possibly have evolved as a response to cancer.
In practice, the term "tumor suppressor" generally means a gene for which recessive loss of function mutations are associated with cancer (i.e. you have to lose function of both copies of the gene in the same cell before there's an effect), while "oncogene" means a gene for which dominant gain of function mutations are associated with cancer (i.e. mutation in one copy of the gene is sufficient to have an effect). Neither term implies anything about how the gene evolved or whether selection due to cancer was a factor in the evolution of the gene.
While most of what you say is generally consistent with mainstream science (including my copy of Cancer by Weinberg, AKA, "the bible"), it neither refutes my point, nor provides any support for the parent poster's claim.
Also, "DNA-repair proteins pre-date the evolution of multicellular organisms, so they cannot possibly have evolved as a response to cancer." is not a valid argument. There are eukaryotic DNA repair proteins not found in bacteria, for which evolutionary evidence shows they evolved more recently. A number of such genes aren't just DNA repair, but cell cycle controllers that respond to DNA damage and coordinate complex activity. Whether they are "sole purpose of preventing cancer", is a very deep question, and goes to the heart of the nature of cancer. For example, naked mole rats either never or very rarely get cancer; current thinking is that hyaluronase they produce has a protective effect. Did the genes that make enzymes that produce hyaluronase evolve "specifically to prevent cancer", or did they play other roles and just incidentally provide cancer protection? Those are challenging hypotheses to express and prove either way.
I'm sure you're familiar with the Hallmarks of Cancer.
I think you are arguing on two different levels. I'm a professor biologist and though it strikes me as a pretty indirect mechanism (arguing the effect size could be small), I see some merit to the commenter's idea.
The current hypothesis is that humans have a longer lifespan because having living grandparents conferred a survival advantage over having only parents. Arguing that elderly relatives confer a disadvantage would seem to directly contradict that hypothesis, unless somehow grandparents were beneficial but great grandparents were not.
I would argue that cancer is more of a consequence of aging, genetics, and environmental factors and not a "feature". Cells have evolved multiple mechanisms to prevent rampant and uncontrolled growth. With cancer these mechanisms are perturbed through genetic alterations due to "bad luck" or the consequences I mentioned previously.
You can also think of cancer as a consequence of multicellularity.
Multicellular organisms need checks on how often and by how much a group of their cells can multiply. A liver must contain a specific amount of liver cells, and cancer occurs when these cells are able to continually divide and eventually activate non liver specific genes.
The cells of a multicellular organism become highly altruistic because each cell of the organism gives up its ability to reproduce in order to provide a chance for the organism's gametes to produce a new living organism.
So wyldfire's original comment on Cancer being a 'feature' is not necessarily incorrect, however the explanation is.
Cancer occurs when the contract that states that the Liver cells, who cannot reproduce, become able to continually divide without checks and balances. You can also almost think of Cancer as Cellular natural selection and evolution within the body. Cancer is a feature and consequence of multicellularity and likely not adaptive in any way such as sickle cell anemia and malaria resistance.
The fact that every cancer is different and arises due to the accumulation of random mutations is strong evidence that it is the result of dysregulation, not a regulated process. If it was adaptive to have an age-limiting "kill switch", there are much more direct ways to achieve that. (e.g.: https://en.wikipedia.org/wiki/Bamboo#Mass_flowering)
you could argue that, most evolution conclusions are based on visible outcomes and the assumption it has utility, rather than actually proving it has more utility over a failed line of evolution that researchers will never see
I would like to point out that many mammals have more genetic safe guards than humans do against cancer cells, so my conclusion is that humans have a flaw
For background, dendritic cells are a type of antigen-presenting cells, which means their job is to pick up proteins, break them up into small pieces (antigens), and then show those pieces to T-cells, whereupon the T-cells can either say "looks like a self antigen, everything's fine" or say "that looks like a foreign antigen, raise the alarm!" and then initiate a specific immune response against that antigen.
The basic concept here is that if you have a specific protein that you want to raise an immune response against, you can do so by tricking dendritic cells into producing copies of that protein, which will then get presented along with all the other antigens for inspection by T-cells. You can pull off this trick by feeding RNA that encodes the target protein to the dendritic cells, and as a bonus, the fact that there's free RNA floating around triggers anti-viral defenses, which causes the T-cells to be extra suspicious of the antigens they're inspecting (i.e. it lowers their threshold for raising an immune response). But injecting RNA directly into your spleen isn't exactly practical, so instead they found that attaching the negatively charged RNA to some positively charged lipids in a specific ratio (which results in a specific ratio of charge to mass) causes them to localize to the spleen and then get taken up, translated, and presented by dendritic cells when injected intravenously.
So, put it all together, and the workflow for treating cancer looks something like this:
1. Find a protein produced by the cancer cells that is either sufficiently different from the same protein in normal cells (due to mutation) or not produced in normal cells.
2. Construct an RNA transcript that will produce that protein when translated.
3. Attach that RNA transcript to the liposomes in the appropriate ratio, and inject it into your bloodstream.
4. Let the immune system do its thing.
5. Repeat as necessary to keep the immune response active until it's killed all the cancer.
Obviously step 1 is still the hard part, and the paper chose as a proof of concept two example cancers for which this step was already done. But finding a viable cancer-specific antigen is certainly orders of magnitude easier than determining the mechanism of a cancer and then developing a treatment specific to that mechanism.