Cancer therapy by RNA delivery to dendritic cells
nature.com
nature.com
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.
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.
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.
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.
Company release: http://biontech.de/2016/06/01/nature-publication-describes-f...
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.
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.
Not sure if that's intentional, but the BioNTech series of trials for melanoma been called MERIT (this particular incarnation is Lipo-MERIT).
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.
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.
An awesome book which touches on this in addition to other history or cancer is The Emperor of all Maladies http://www.amazon.com/Emperor-All-Maladies-Biography-Cancer/...
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.
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.
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.
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.
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.
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.
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.
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