How We May Soon Vaccinate Against Skin Cancer

Source: Medium, Sam Westreich, PhD
Photo: You, to immune cells: “Go through this field and trim any tulips that turn red. Those are the bad ones.” (Rupert Britton on Unsplash)

If cancer is unique to each person, how do we make a vaccine to stop it?

Working together, Merck and Moderna have created a new vaccine that seems to offer a significant advantage for patients suffering from aggressive melanoma skin cancer. When taken in conjunction with Keytruda, this vaccine offered an increased chance of preventing the cancer from returning:

22.4% of them (24 participants out of 107) saw cancer return with Keytruda + the new vaccine.
40% (20 out of 50) saw the cancer return with just Keytruda alone.
This isn’t full protection, the same way as polio or smallpox vaccines protect us. But that is still a significant improvement.

But this raises a question. How, exactly, can you vaccinate against cancer?

The challenge is that cancers are each nearly unique, with many different subtypes. Cancer has been described as a “hydra with a thousand heads”, due to its complexity.

So today, let’s give a quick, high-level, easy-to-understand overview of why cancer is so difficult to immunize against. Then, we’ll talk about how this vaccine works — and why it’s not going to be as easily distributed to the population compared to most vaccines.

Cancer is a category, not a specific disease

We use the term “cancer” broadly, but even in everyday conversation, we know that there are different types, and that the type of cancer has a big impact on its seriousness.

Consider how drastically 5-year survival rates vary for different cancers. If you have breast cancer, you’ve got a 91% chance of still being alive, 5 years later. If you’ve got pancreatic cancer, it’s a much less optimistic 12% chance of still being alive after 5 years.

Even beyond the organ, there are more specific types still. When it comes to breast cancer, for example, we have ductal carcinomas, invasive carcinomas, inflammatory cancer, triple-negative cancer, and still more types. Each of these is slightly different — and a treatment plan that will work well for one type may not perform as effectively on another type.

For example, let’s take triple-negative breast cancer. The name comes from the fact that these breast cancer cells don’t have any of the 3 most common traits of breast cancer:

They don’t have estrogen receptors on their outer surface;
They don’t have progesterone receptors on their outer surface;
They don’t make large amounts of a protein called HER2, which is a common target in breast cancer tests.

This limits the treatment options; other cancers can be treated by interfering with hormone levels, but these tumors aren’t even sensing those changes (given the lack of receptors). Additionally, we can’t use HER2 inhibitors to target these cancer cells, because they aren’t making lots of the HER2 protein in the first place.

There are similar variations and flavors of other types of cancer (lung cancer, brain cancer, stomach cancer, pancreatic cancer, colon cancer, bone cancer, skin cancer… the list goes on…).

Put it all together, and we can see that “cancer” is really a header on an entire family of diseases. It describes the mechanism of our own cells growing out of control, but it can happen in many ways in many different types of cells in our body.

So if every cancer case is distinct and unique… how do you create a wide-scale treatment that targets all cases?

The secret is: you don’t.

Building a vaccine for a single person

In this clinical trial, each patient received a different, unique vaccine. In essence, each vaccine dose was crafted for one person, and one person only.

The researchers collected samples of each patient’s tumors through surgical removal (biopsy), and then analyzed them to identify which proteins present on the outsides of the cells had identifiable mutations. They then built the vaccine dose for that person to specifically target the proteins with identifiable mutations.

Each vaccine included targeting instructions for multiple specific mutated proteins that were present in that individual. John Doe, for example, had cancer cells with mutated proteins A, C, and D, while Jane Doe had cancer cells with mutated proteins C, F, and G. John and Jane each received custom vaccines to teach their immune systems to specifically target the mutations present in their individual tumors.

The secret to this? A breakthrough from COVID: messenger RNA, or mRNA.

With our previous model of vaccines, we had to provide each mutated protein, so that our immune system could learn to identify and destroy it. But now, with mRNA, we simply provide the short-lived RNA blueprint for the mutated protein. The immune cells make the protein themselves, identify it, and then destroy it!

It’s much faster for us to produce a specific mRNA than it is for us to produce the specific mutated protein. That’s what enables this vaccine to be created, personalized for each individual. Some individuals received an mRNA cocktail that trained their immune system to target more than 30 different malformed proteins present on their previous tumors!

What are the limitations of this approach?

I can practically hear you through the screen: “Great, so we’ve got a vaccine against cancer, but it has to be custom made. I bet this is going to set up a greater divide between the elites and the working class.”

Well, let’s not get too far ahead of ourselves. This new approach shows promise, but it’s got a number of limitations that we’ll need to confront before we start worrying about GATTACA situations.

First, perhaps the most significant: in order to learn what proteins should be targeted by the vaccine, we need a tumor sample.

That means that you have to have already had cancer, and survived it.

This vaccine approach won’t work for fresh-faced 18-year-olds planning on spending all day of every college spring break sitting out on the beach, soaking up rays. Since they haven’t yet had any skin cancer, we don’t know what genes are most likely to go haywire in their systems, and thus what proteins we should train their immune system to monitor.

Second, this approach isn’t bulletproof. Again, this was a smaller study, and while the decrease in returning cancer rates was significant (22.4% recurrence, versus the currently-best-available market alternative at 40% recurrence), it’s not a guaranteed defense.

We also don’t know how well this approach will hold up in larger trials. There were only 157 total participants in this study, and at a larger scale, we may see that the treatment is less effective or that it is more likely to fail when certain other conditions are present.

Finally, there is the final hurdle: cost. It’s unclear how much a therapy like this could cost, but given that it requires specific analysis and sequencing of the tumor biopsies, plus custom mRNA creation, it’s probably not going to be as affordable as a small molecule drug that can be mass produced for thousands of patients at once.

In summary: targeting recurring cancers with custom vaccines shows promise

We have cancer-related vaccines, but in the past, they’ve targeted pathogens that are known to cause cancer as a secondary effect — not targeting the cancer itself. The HPV vaccine, for instance, is targeting the human papilloma virus, because that virus is capable of leading to cancer as a side effect.

Now, we’ve got a vaccine that specifically targets a cancer; it trains our immune system to recognize the malformed proteins in the tumors of patients with melanomas, so the immune system can help stamp out that cancer if it returns in the future.

The technique requires a custom design of mRNA for each individual, so this won’t be widely rolled out like the COVID or measles vaccines. It also needs to be built based on an existing tumor, so it only helps cancer survivors avoid recurrence.

Still, it’s a powerful new tool to help cancer survivors live with less fear of the disease returning! And it’s a great new application of the mRNA technology for rapid vaccine development.

But it’s no excuse to skip on the sunscreen!

https://medium.com/a-microbiome-scientist-at-large/how-we-may-soon-vaccinate-against-skin-cancer