The vaccine technology America learned about during the pandemic was originally aimed at cancer, but its use against infectious diseases took off in the pandemic. Now a new study suggests specially designed mRNA shots can help prevent recurrences of melanoma, a dreaded skin cancer.
The study, presented Sunday at a research conference, showed that after nearly two years, patients who received a personalized mRNA vaccine made by Moderna and Merck were 44% more likely to be alive and avoid new tumors than those who received only the standard of care.
If the results hold up in a larger, longer study planned to start later this year, it will mark a dramatic turnaround for cancer vaccines, which have been tested and failed for decades.
“It’s probably the first real data that suggests that this personalized approach to vaccination may be worth exploring further,” said Dr. Ryan Sullivan, an oncologist at Mass General Cancer Center, who was a co-author on the study.
Instead of using a vaccine to try to prevent or shrink a tumor, the new mRNA vaccines are aimed at reducing the chances of a high-risk cancer recurring.
“This represents a big shift in how we’re using cancer vaccines,” said Dr. Robert Vonderheide, who was not involved in the study but is the program committee chair of the American Association for Cancer Research’s annual meeting, where the study was presented.
The pandemic proved that mRNA vaccines, already in development for cancer, could be used safely and developed quickly, said Vonderheide, who also directs the Abramson Cancer Center at the University of Pennsylvania.
Benefits seen in melanoma, a cancer known to be controlled by the immune system, are likely to hold up in other cancers that are affected by the immune system, he and several other experts said. The next one to be tested will be non-small-cell lung cancer, which kills about 100,000 Americans a year.
But it made sense to try first in melanoma.
“No cancer is as immunotherapy sensitive as melanoma is,” said Dr. Rodabe Amaria, a melanoma oncologist at MD Anderson Cancer Center in Houston, who was not involved in the study. “You have to prove it in melanoma before you try it in other cancers.”
How would an mRNA cancer vaccine work?
These vaccines are designed to prevent cancer recurrences, not an initial run-in with the disease.
After surgical removal of a tumor or a separate biopsy, scientists send a sample of tissue and blood for genetic sequencing, looking for proteins that are unique to the cancer and not present in healthy tissue.
The mRNA vaccine is then designed to target 34 of these distinctive proteins, getting the immune system to recognize them and hopefully kill the cells that make them without damaging healthy tissue.
Because there are so many possible neoantigens, resulting from a patient’s own genetics and the evolution of their tumor cells, the vaccine must be bespoke, designed specifically for each person.
Researchers aren’t sure how many neoantigens to target or which are likely to offer the most benefit, “so we cram in as many potential neoantigens as possible,” said Dr. Eliav Barr, chief medical officer of Merck, which supported the trial.
Each vaccine takes about eight weeks to manufacture and is based on tumor cells removed during surgery. While the patient waits for their personalized vaccine, they start taking the drug pembrolizumab (brand name Keytruda), made by Merck, which unleashes the immune system to attack cancer.
Pembrolizumab is given as a 30-minute infusion every three weeks for a year. Patients receive two or three doses of pembrolizumab and then, when their vaccine is ready, they get nine doses along with their next nine infusions, before completing pembrolizumab.
According to findings released Sunday by the researchers, but not yet peer reviewed, among 107 volunteers who received both the experimental vaccine and pembrolizumab, the cancer returned in 24 (22%) within two years. There were 20 recurrences (40%) among the 50 people who received only pembrolizumab.
(Keytruda sells for a list price of $185,000 a year, although most people will not pay the list price, according to Merck. It’s too soon to know how much companies will charge for mRNA vaccines.)
Melanoma is diagnosed in about 100,000 Americans per year. If caught early, nearly everyone survives for at least five years, but only one-third of patients whose cancer has spread widely survive that long.
“Pembro” already dramatically decreased recurrences, but the new study showed a 44% extra benefit with the addition of the mRNA vaccine, called mRNA-4157/V940.
“We’re already reaping those benefits (from pembro), and now, in such a short period of time to have an additional therapeutic agent that builds on that progress is a very exciting thing,” Amaria said.
Side effects of mRNA vaccine for cancer
The addition of the mRNA vaccine did not seem to add substantially to the side effects already seen with pembrolizumab.
Pembro often affects the endocrine system, Amaria said, causing diabetes and potentially permanent thyroid problems. Other common side effects include exhaustion, muscle pain, rash, diarrhea, fever, cough, decreased appetite, itching, shortness of breath, constipation and nausea.
As more patients live longer with melanoma, these side effects are becoming more noticeable, Amaria said. “In some patients, the benefit goes hand-in-hand with the toxicity,” so side effects may be a sign the treatment is working.
“In some patients, we’re fundamentally changing their quality of life,” she said, but “most people do have normal lives, recovered from side effects.”
What is mRNA?
Messenger RNA carries instructions from a cell’s DNA code to the cellular machinery that manufactures proteins, telling it what to make. Delivered as a vaccine, the short-lived mRNA turns cells into factories that produce desired proteins.
With COVID, mRNA vaccines produce the spike protein found on the surface of the SARS-CoV-2 virus, training the immune system to recognize and wipe out viral cells.
In the case of these cancer vaccines, the mRNA triggers the body to produce the 34 neoantigens, training the immune system to recognize and target them.
In cancers that have spread beyond an initial tumor, surgeons can’t remove all the cancerous cells. In people with Stage 2 melanoma or above, this dangerous spread has already begun and the risk of recurrence after surgery is very high.
The vaccine should help prevent these dangerous recurrences, Barr said.
The mRNA vaccine can’t be used to prevent disease, as it is with COVID, because the neoantigens don’t exist until the tumor does, Barr said. But it appears to work well when designed to target a specific person’s cancer and hopefully providing long-term memory, so even future cancer cells will be killed.
BioNTech, the German company that helped develop the other mRNA vaccine against COVID, is also working on cancer vaccines, including against ovarian and lung cancer, as are several other companies.
It’s not really clear why an mRNA vaccine would be effective against cancer when so many other approaches have failed, several experts said. The technology may simply spur more reaction from tumors, Sullivan said.
What happens next?
The new study, launched in 2018, was relatively small and only lasted a few years, so Merck hopes to start a large, Phase 3 trial later this year. It will be open to people with Stage 2 or Stage 3 melanoma.
Amaria said she and her colleagues at MD Anderson are considering participating. Patients often come to her asking for an mRNA vaccine against their cancer, she said.
Dr. Jeffrey Weber, who led the new study and is the deputy director of the Perlmutter Cancer Center at NYU Langone, said he’s optimistic about the future of mRNA vaccines against cancer.
“It’s got a ways to go, but I do believe that these results will hold up over time,” he said.
