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Comment by monocasa | Hacker News Reader

I don't quite follow. The whole shtick with problem cancers is that your immune system is ignoring them for whatever reason. mRNA vaccines work by priming the immune system for something it would attack anyway, but under safer circumstances since there's no real virus in the vaccine. What can the mRNA create that the immune system will train on given that the immune system isn't attacking the real thing to begin with?

(And to be clear, this obviously is a piece I'm missing rather than a hole I'm trying to punch in their work. They're way smarter than me and wouldn't be working on this unless they had a clear idea)

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It sounds like you are conflating the antiviral implementation with what the mRNA technology itself is doing. mRNA acts as a blueprint for proteins. Your body has tRNA translation complexes that "read" the mRNA and appropriate the correct amino acid to add to the protein chain. Here is a more detailed description - translation begins about halfway down with the UGCAs: https://www.nature.com/scitable/topicpage/translation-dna-to...

So basically the mRNA tech is a means of delivering protein blueprints for in vivo production using your bodies natural machinery. In the case of COVID-19, this was used to manufacture spike protein, which attracts the body's immune response.

I'm not an expert on the best way to use the tech with cancer, but I could imagine a number of different approaches - targeted inducing of cell death, "painting the target" for chemo drugs, making things like monoclonal (designer) antibodies in-vivo, etc. The silver bullet is that it eliminates all of the complexity of creating and storing advanced biologics outside the body. Now you just deliver a bit of code and your body does it's thing.

> the correct protein to add to the chain.

Slight error: it adds an amino acid to the chain. The chain itself is/will fold into a protein.

That is true, thanks for the correction.

> I could imagine a number of different approaches - targeted inducing of cell death, "painting the target" for chemo drugs, making things like monoclonal (designer) antibodies in-vivo, etc.

The article does explicitly call it a "cancer vaccine" (direct quote from the researcher) and says "the same principle [as the COVID-19 vaccine] can be applied to get the immune system to take on tumours".

That's more specific than sneaking in with mRNA to get the body to produce something. It definitely sounds like whatever it is, it gets the immune system involved. It seems fair to ask exactly how it does this.

Scientists are already showing some promising results using the immune system against tumors. See for example:

https://en.m.wikipedia.org/wiki/Pembrolizumab

The promise of mRNA is the potential to prompt the body to produce the therapeutic antibodies itself, rather than produce them externally and injecting regularly.

> That's more specific than sneaking in with mRNA to get the body to produce something.

No, it really isn't more than that. You could send mRNA code into the body that produces a designer antibody that is specific to the cancer a patient has (similar to CAR-T, Keytruda, etc.), or you could design mRNA that specifically causes cancer cells to express antigens that attract the immune system. I'm obviously oversimplifying a pinnacle of human achievement, but on paper it should work that way.

Are cancer cells distinct from other cells?

To a certain extent because they need to consume vast amounts of resources. It's not perfect though so it's generally assumed that every type of chemotherapy has collateral damage of some sort as regular cells also get accidentally killed.

For certain definitions of distinct, yes. Not as distinct as a bacteria cell vs. a human cell, so you have to be more careful selecting a target. For example, antibiotics and chemotherapy both affect cell reproduction, but antibiotics have fewer major side-effects than chemotherapy - the targets on bacteria aren't present on human cells (though they are sometimes present in the good bacteria in your gut). Chemo targets cells that use the same mechanisms as health cells, thus the side effects. Since cancers are driven by mutations at the genetic level, the goal would be to find a specific mutated site (or a combination of sites) to target that would allow specific delivery of drugs or markers or whatever.

If you can find specific sites, you can design a complimentary piece of RNA code to bind it and allow the drug delivery mechanism to do it's thing. Way fewer side effects versus systemic delivery.

off the top of my head:

cancer cells have distinctive traits that can be exploited for targeting [1]. A fairly elegant approach is to use a vesicle studded with antibodies to the tumor antigen to get the payload to the bad cells, the mRNA is then endocytosed into the tumor cell, expressed and the protien product adorns the tumor cell. when this is an antigen such one sees with measles there would be a long lasting immune response that would look for any cells with this antigen [i.e. target tumor cells]

[1] https://en.wikipedia.org/wiki/Tumor_antigen

I don’t know the biology, but mRNA vaccines has been used for cancer for some years now. I wish this message was louder and clearer because people seem to think covid is the first use of the technology.

My very basic understanding is you customise the mRNA payload towards the immune system targetting the mutating cells that have caused cancer in a patient (after the cancer material has been surgically removed). This prevents the cancer from re-occuring.

Right, but the immune system already wasn't responding to the mutated cells, and was obviously exposed to any proteins that would identify them.

commented up thread a couple posts:

https://news.ycombinator.com/item?id=26518258

Use of mRNA is a much more generalized technique than just producing an immune response. In fact part of the problem in making them an effective delivery system for other therapeutics is trying to avoid triggering an immune response.

I believe the advantage of the mRNA method is that it’s somewhat generic: you can stick any (protein-coding) RNA fragment into it, and it will be expressed in the body and picked up as a target by the immune system if it has any potential for the latter (I. e. isn’t something that’s ubiquitous in the body already)

As such, it is faster to get from idea to vaccine. Recent history is an example already, but the cycle will be improved dramatically considering the technology is very much still in infancy. It’s also cheaper, to the point that producing ten doses of ten different vaccines may not be more expensive than producing a hundred doses of a single vaccine. This will be helpful against “cancer” which is closer to an unlimited number of different diseases than a single target.

I was wondering the same thing. Vaccination means exercising against a mockup foe before meeting the real enemy. But the cancer patient is already deep into the battle, how could adding mockup enemies help winning?

Perhaps the molecules they want the immune system to attack aren't sufficiently mobile, sticking to the tumor instead of diffusing into the entire body?

From what I've picked up in the pandemic the immune system has a dedicated proving ground spots where experimentation is happening, and relies on special cells to transport foe candidates into those proving grounds (just like a programmer would gather problematic input samples in their unit tests). Maybe the tumor bits they want attacked cannot be transported to "lab organ", but fragments created separately, from mRNA injections, could, and once the immune system is producing antibodies against those fragments they will also react with the immobile real tumor bits.

Purely speculative on my part, but maybe it really is something along those lines?

The core issue with cancer is that the immune system does not combat the tumor. Cancer patients suffer from damage caused by the tumor and by aggressive therapies.

Cancerous mutations happen all the time. Usually, the affected cells either

* repair the damage, * get wrecked by the damage's side effects, * suicide or * get blasted by the immune system because the mutation alters their surface proteins in weird ways.

Tumors form because the cancerous mutations succeed to fly under the radar of the immune system. mRNA therapy can be used to make the immune system target specific surface features of cancer cells, or to do something else in connection with the cancer cells that attracts the immune system's attention.

Just a newbie question: Would it be beneficial that body itself generates transcriptional repressor proteins (via mRNA vaccine) that bind to specific cancerous mutation genes instead of giving some medicine that has similar inhibitory goals?

(Sorry, I'm just trying to learn cell biology on my own.)

it is difficult enough to target a cell and deliver to the cytoplasm, when you attempt to move further and deliver to the nucleus this is further difficulty. if you are certain you have a specificly targeted delivery that stays away from non cancerous cells you can use mRNA to create labels [antigens] on the cell surface that the immune system interprets as pathogenic, thus immuno targeting oncocytes for destruction.

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