this post was submitted on 02 Jan 2024
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I never once thought about it before but how do they select a target antigen for what is effectively a human cell? Maybe they could take a similar approach to Rabies or Prion Disease.
The target antigens are from human cells, but they are human cells that mutated and hence became cancerous. What Moderna does, is it takes DNA from these cells, sequences it and finds where exactly the mutations occurred. A mutation means that there is a different sequence of amino acids in a protein, which in effect makes it a new and distinct antigen. This way, they select antigens that are present in the melanoma cells, but not in normal cells of the body. Then they take these mutated sites and use them to generate mRNA that will encode them all, be used to synthesise these mutated antigens, and train the immune system to react to them as alien antigens. The treatment described in this article is a combination of the mRNA vaccine with Keytruda, which is a cancer therapy based on an antibody. The antibody targets a protein from the PD-1 / PD-L1 axis. This axis is used by normal cells to tell the immune system not to attack those cells, because they are body's own cells. Cancer cells often mutate like crazy, but then exploit this PD-1 / PD-L1 axis basically to say to the immune system "nothing to see here".
As for Rabies, I think we already have pretty well working vaccines, so we're not really in a dire need for new ones.
As for prions, it would be tricky. The reason prions do what they do is not that they are mutated proteins, but misfolded proteins. This is to say they assume the wrong shape, even though the sequence of amino acids in them is the same as in the healthy version of the protein. And this in turn means that they were synthesised based on a healthy, unmutated version of mRNA. And this in turn means that there is no mutation that the Moderna vaccine strategy could employ to train the immune system to recognise that prion protein.
Holy shit, this is a type of down to earth, factual and enlightening comment that we used to get in reddit! Thanks for this!
Thank you for the kind reaction.
I recently moved from Reddit to Lemmy (same username) and I took my comments with me.
Obligatory: username checks out
Seriously though, thank you!
edit …also: fuck cancer
Agreed. And I was happy the comment didn't end with, "in 1998, Hell in a Cell...".
It's not necessarily impossible to target prions but it doesn't seem trivial. The reason they're dangerous is specifically the incorrect shape because that shape changes interaction behavior with other biological molecules, and immune cells could theoretically test for that change in interaction. But that's more complicated than regular molecule recognition which immune cells normally do. There's probably research in trying to make immune cells handle that too, but I haven't seen any articles about it.
If it's based off mutated dna do they have to tailor a vaccine to each case? Or do cells mutate the same way every time?
They have to manufacture it unique to the individual. Luckily, manufacturing custom mRNA is not very expensive.
That's really cool that they can do that. Kind of reminds me of something out of Star Trek when they have to "synthesize a cure" or whatever for some space disease.
Especially compared to normal cancer treatment
In general, mutations can happen anywhere on any gene, so every patient's cancer will have its unique signature of mutations. However, like in the evolution of organisms by natural selection, most random mutations will have a detrimental effect and the cells carrying it will die. Some of the mutations will be neutral and despite the change in the amino acid, the cells harbouring it won't survive better or worse than cells that don't have it. But a few mutations will make the cancer cells proliferate faster or evade the immune system better, which will lead to these cells surviving and ultimately overtaking the population of the cancer cells. The latter mutations often happen in the same places on the same genes, and in melanoma for example, in as many as 41% of cases the 600th amino acid in a protein called BRAF mutates from valine to alanine (so the code for that mutation is "BRAF V600E"), and BRAF is only one example of such genes that commonly mutate in the same position.
So to answer your question - I don't know Moderna's exact protocol, but my guess is that the tailored vaccine will contain a mixture of these commonly occurring mutations and some mutations that are unique to the patient.
Just on the rabies bit, there has been a couple of trials using mRNA vaccines on rabies. They've shown promise as they have been shown to be quite effective, and the current rabies vaccines we have are expensive and time consuming to make.
Yes.
What you proposed just doesn't feel like the sort of thing we've come to expect from modern medical research, if it was outright targeting selective genetic information then it would be banned in many many countries, and maybe it should be just for it's potential to become a weapon. No other commercially available mRNA Vaccines ever touched human DNA in that manner. It has always been some other protein structure to be identified by the immune system.
I think the first point to make is that this is not really the patient's own genetic information, but that of their cancer, something they desperately want to get rid of. And the second point is that to my knowledge, there is no county on earth, where taking part in a clinical trial would not require the patient's consent, which is to say, all people in the study were informed that the genetic sequences of their cancers will be analysed and used to generate a vaccine.
As for the potential to become a weapon, you would have to elaborate, because I really don't see how the Moderna vaccine strategy could be weaponised.
If a mutation occurs making a cell cancerous then what has changed is human DNA. We're creating technology that can turn immune systems against cells containing specific proteins in human DNA. I think curing cancer is good and maybe even necessary but if creating targets within human DNA is what Moderna is doing then it needs to be strictly controlled and regulated.
Here is a wild hypothetical for you: if you can target the parts of human DNA that make a cell cancerous then in theory you could target parts of DNA that make a person black or target cells in people with green eyes.
Of course it needs to be controlled and regulated. Like any other drugs. One of the reasons drugs are expensive is because there is so many regulatory hurdles that drug makes have to deal with before they can touch a patient.
I get your hypothetical, but it has two shortcomings. Firstly, training the immune system against cancer mutations is fairly easy, because the mutations are not present during the process of T and B cell maturation, so in the population of circulating naive T and B cells in a patient, there are likely to exist ones that are going to recognise the cancer antigen. Whatever proteins drive the dark pigmentation of skin or green eye colour will be used to drive the negative selection of T and B cells in the person with dark skin or brown eyes. And so, even if you administer a "vaccine" encoding these proteins, their immune systems will not be able to mount a response against them.
Secondly, what about the practicalities. Say you made the anti-green eye vaccine - how do you administer it to people? I'm assuming we're not talking about some dystopian future where forcing people to receive injections that contain biologicals killing them is legal. It's not the kind of "vaccine" that you could just spread in the air or add to drinking water for it to take effect.
I think far moreso than any other drug, regulations for drugs in the USA is shit. It needs to be regulated as if it were already a weapon.
Secondly, the nature of mRNA delivery through nanolipids opens up the possibility for oral delivery instead of only injection, a large amount of research is going into that.
BioNTech is doing something similar. Their approach (and likely also Moderna's approach) works by first identifying mutations in protein coding genes in the cancer cells. Then, they target the resulting mutated protein (that is distinct from the same protein in non-cancer calls) with their vaccines.