
Cancer therapy by RNA delivery to dendritic cells - kaivi
http://www.nature.com/articles/nature18300
======
rcthompson
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.

~~~
pvnick
Great summary, thanks for that. This therapy appears fairly elegant. Let's
hope it makes it through trials.

~~~
rcthompson
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.

~~~
muditjai
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.

~~~
rcthompson
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.

------
baldfat
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.

~~~
Aelinsaar
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.

~~~
baldfat
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.

~~~
Aelinsaar
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.

------
superfx
Here's the full article for those interested:
[http://rdcu.be/iFZr](http://rdcu.be/iFZr)

~~~
baldfat
Thank you for the link

------
reasonattlm
Paper:
[http://dx.doi.org/10.1038/nature18300](http://dx.doi.org/10.1038/nature18300)

Company release: [http://biontech.de/2016/06/01/nature-publication-
describes-f...](http://biontech.de/2016/06/01/nature-publication-describes-
first-example-of-a-clinically-applicable-and-systemic-mrna-cancer-
immunotherapy-vaccine/)

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.

~~~
hanklazard
>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.

------
pessimist
To keep things in perspective, in oncology the current success rate of
treatments that enter trials is just 5%! See
[http://blogs.sciencemag.org/pipeline/archives/2016/06/02/are...](http://blogs.sciencemag.org/pipeline/archives/2016/06/02/are-
things-getting-any-better-in-the-clinic).

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.

~~~
danieltillett
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.

------
brudgers
The breaking story in the popular press:
[http://www.independent.co.uk/news/science/cancer-vaccine-
imm...](http://www.independent.co.uk/news/science/cancer-vaccine-
immunotherapy-universal-immune-system-rna-nature-journal-a7060181.html)

------
teekert
This link does work, assuming it is the same article:
[http://www.nature.com/nature/journal/vaop/ncurrent/full/natu...](http://www.nature.com/nature/journal/vaop/ncurrent/full/nature18300.html)

~~~
VSerge
thanks

------
wyldfire
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?

~~~
Houshalter
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.

~~~
dekhn
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.

~~~
Houshalter
>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...](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.

~~~
dekhn
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.

