Today’s episode is made in partnership with PancOne, an international network of world-class cancer research institutions looking to increase the survival rate for Pancreatic Cancer.

If you’re interested in learning more or are able to donate to their research, head over to www. PancOne.org or click the link in the description. [ intro ].

Around the turn of the 21st century, researchers finally found evidence for a hypothesis that had been around for a while:. In addition to protecting us from diseases, our immune system helps to protect our body from itself… by watching out for cancer. And that of course raises the question:.

Could we give our immune systems a leg up in spotting tumors? Could we develop vaccines for cancer? The idea is fairly new, but there are already two cancer vaccines on the market.

And researchers are looking to up that number with a technology that promises to be cheaper, faster, and more customizable than traditional approaches: vaccines based on RNA. Traditional vaccines expose our body to antigens: proteins or sugars derived from pathogens like viruses and bacteria, which our immune system can recognize, learn from, and use to attack a real invader. In cancer vaccines, those antigens come from tumor cells instead, but the idea is the same:.

We want to train our immune systems to find those antigens and clear out the tumor they were derived from. One approach is to use whole tumor cells, taken from a patient and modified to serve as training wheels for their immune system. Others only use the antigens from the patient's tumors.

But cells and bits of protein aren’t our only options. Enter vaccines based on the genetic code -- the nucleic acids DNA and RNA. This approach is meant to be faster and easier than traditional vaccine development.

DNA and RNA vaccines reprogram cells to churn out that antigen without having to expose our immune system to any external proteins or invaders. With DNA vaccines, you make a DNA molecule that carries instructions for the cell to make some antigen, using the same genetic code and protein-making machinery it already runs on. Then, you stick it in the cell's nucleus somehow.

After that, the cell copies those instructions in the form of a piece of RNA, which travels outside the nucleus to where all the proteins are made. And finally, the cell starts pumping out antigens. Meanwhile, with an RNA vaccine, you just skip those first steps and put the instructions on the RNA molecule to begin with.

The idea is that we can very easily put together nucleic acid molecules to code for whatever we like in the lab -- not so with proteins or whole tumor cells. So this approach is fast, and it can be tailored to whatever we like. There aren’t a huge number of these things kicking around yet.

While some DNA vaccines are approved for veterinary use, more and more research focuses on RNA instead. And that’s because it’s harder to get the DNA where it needs to be, inside the cell’s nucleus, where it’s going to be turned into RNA and then sent back out to make the antigen we want. And once the DNA gets there, it can cause problems.

Like, sometimes, the cell can incorporate loose DNA into its chromosomes, and it’s not picky about where. Rarely, that can interrupt other genetic material you really need -- and, ironically, that’s a step toward cancer. Something to avoid in a cancer vaccine.

But RNA vaccines skip this step, since they’re a ready-made recipe for a protein antigen we want. And since they’re RNA, there’s no need for them to go into the nucleus to do their thing. Both DNA and RNA vaccines have been studied since the 1990s, and the first RNA cancer vaccine was approved for human trials in 1997.

But RNA is actually a pretty delicate molecule. It wasn’t until 2008 that we learned how to make the RNA in a vaccine stable enough to easily get it inside cells, by chemically modifying some of its components. Since then, RNA vaccine technology has been progressing by leaps and bounds, and a lot of RNA cancer vaccines have already shown promising results in human trials.

For example, in a small early clinical trial of an RNA cancer vaccine in Germany conducted on 13 melanoma patients, there was an immune response against the cancer in all of them. And in two of the patients, the vaccine shrunk their tumors. And another clinical test of an RNA melanoma vaccine, developed in Belgium, showed significant tumor reduction in 15 out of the 39 patients in a more advanced trial.

Which means these two, and maybe others, could be coming to a hospital near you. But if they’re so great, why aren’t RNA vaccines everywhere already? Well, any vaccine can be set back in clinical trials by safety issues or side effects.

But cancer vaccines face some potential additional snags. It’s often pointed out that “cancer” isn’t really one disease, and that’s true. Which means you can’t design one vaccine, or half a dozen.

In fact, any given vaccine is likely to be effective only in patients with very specific cancers -- because every type is likely to have different antigens. So you need your clinical trial participants to have that exact cancer. Say, not just melanoma, but melanoma of the eye, which only happens in one out of ten thousand people.

And on top of that, there are other factors that may exclude candidates from the trial, like having serious conditions other than cancer that could complicate the results. So that makes cancer vaccine trials extremely hard to recruit for, and it also means that each phase of the clinical trials takes an extra long time to complete. When you look at it that way, we’ve actually made pretty good progress since the late 2000s.

But what makes things even more difficult are all the ways tumors deflect our immune system. To prevent our immune system from attacking healthy cells, every cell in our body has self-antigens that tell patrolling immune cells “hey, all good,. I super definitely belong here and you shouldn’t murder me.” But for most cancer vaccines, that safety feature is actually a problem.

You see, a lot of the antigens that tumor cells make are actually your body’s own self-antigens. That makes sense, because those are the antigens they have the genes to make. Sure, tumor genetics get a bit hinky, so they might make weird self-antigens.

Like, making a lot of the kind of antigens that you mostly only make as a fetus. But those antigens are still proteins that mark the tumor cells as “one of us,” so vaccines based on them have a friendly-fire problem. They can end up damaging healthy tissues as well.

So any vaccine, no matter how futuristic, still needs to find antigens that are specific to the tumor, so it doesn’t end up hurting our body. That’s a tall order. But it’s not impossible.

And that’s thanks to huge progress in genetic sequencing. The first cancer genome was only sequenced in 2008. But since then, researchers have identified a bunch of mutated, novel antigens that tumors make.

There’s a hitch, though. It turns out that most of these new antigens are unique in every single patient. And every tumor makes a bunch of them, so to make sure the vaccine will do its job, you better be ready to hit as many as possible.

And here is where RNA vaccines really shine. See, you can cook up a personalized cancer vaccine using other technologies, but that is way more expensive and time-consuming. Thanks to new, faster sequencing techniques, scientists can quickly identify all of a tumor’s unique mutations, and then use powerful predictive algorithms to figure out which ones it would be best to target.

Unlike in typical vaccine design, they don’t need a lot of tumor cells to do that, which is a good thing because obtaining enough of those can be hard in certain types of cancer. And once you have the gear in place to make RNA vaccines, creating a new one is just a matter of plugging in that new genetic blueprint for the tumor antigens you found. Plus, it’s super easy to pack all of them into a single RNA shot.

So by using RNA, scientists can design a vaccine in a matter of hours, something that takes months for traditional vaccines. And this makes a whole lot of difference, because patients who are getting these experimental cancer vaccines have often exhausted other treatment options, so every minute counts. But there’s one last hurdle.

Even if you know how to tell tumor cells and healthy cells apart, you still need to overcome all the ways that tumors defend themselves from our immune system. Because our immune system does normally counter them -- so tumors have to find ways around it. First of all, they’re built in such a way that it’s hard for immune cells to physically get inside.

Even if they do manage to weasel their way in, the tumor floods them with chemicals to switch them off -- or force them to deactivate other immune cells as they come in! To help them break through a tumor’s immune suppression, cancer vaccines are often combined with things that boost the immune response. Like immune checkpoint inhibitors, which are medications that mess with the ways tumors put our immune cells to sleep.

You can also induce a little bit of inflammation, which calls in immune cells that can pick up the antigen and teach immune cells what their target is. And this is where RNA vaccines have another advantage. Foreign RNA is naturally recognized by our immune system as the traces of a potential virus attack, because many viruses have genomes made of RNA rather than DNA.

Initially, this was a problem for RNA vaccines, because it got researchers worried about serious side effects from the inflammation. But in a classic example of turning a bug into a feature, scientists realized they could balance that immune response so it worked to the vaccine’s advantage. And that makes RNA cancer vaccines even easier to make, because their very nature will help draw in the immune system.

Even though the technology is so new, an RNA cancer vaccine has already entered Phase III human trials -- the last step before approval. This vaccine is meant to target uveal melanoma, or melanoma of the eye, using the patient's tumors' unique antigens. It's currently being tested on 200 volunteers in Germany, and the trial is scheduled to complete in 2023.

Scientists are also experimenting with multiple ways to improve the potency of RNA vaccines, like by making the RNA self-replicate to cook up even more precious antigens for our immune system. All of this progress shows that we’re getting closer to an era of medicine where we can direct our own cells to make any protein our immune system needs. And even though the results we have so far are limited,.

RNA-based cancer vaccines may just be right around the corner. And that could mean treatments for not just melanoma, but all sorts of cancers -- potentially including pancreatic cancer. As we mentioned earlier, this episode is made in partnership with the PancOne Research Network.

They’re composed of institutions like John Hopkins Medicine,. Memorial Sloan Kettering Cancer Center and the Dana-Farber Institute. And they’re hoping to raise $200,000 to better understand pancreatic cancer, accelerate diagnosis, explore new treatment options, and ultimately save more lives.

In 2018, there were more than 450,000 new cases of pancreatic cancer, and on average, this cancer has only a 5-10% five-year survival rate -- the lowest survival rate of all cancers. And that's barely changed in 40 years. So, this is a big project, and their goal to raise the survival rate to 14%.

If you want to learn more about what PancOne is doing or are able to donate to their research, you can find more at www. PancOne.org or click the link in description. We’ve contributed and, if you’re able, hope you’ll consider it, too! [ outro ].