Moderna, Merck Personalized mRNA Vaccine Shows Promise in Late-Stage Melanoma Trial

Drugmakers Moderna and Merck have scored a breakthrough with a personalized cancer vaccine that doctors hope could eventually work against many types of cancer. The companies said their vaccine helped prevent the recurrence and spread of melanoma, the deadliest form of skin cancer. Moderna expects thousands of melanoma patients could benefit within the first few years of the treatment being approved.

There is excitement among researchers because this marks the first positive results in a large, late-stage clinical trial for an mRNA-based cancer therapy, an important milestone for a technology that became widely known through COVID-19 vaccines. More than 1,000 patients with high-risk melanoma took part in the Phase 3 trial. The patients had their tumors surgically removed but remained at high risk of the disease returning. Early results showed the treatment, known as intismeran autogene, extended the length of time the patients remained cancer-free.

Seth Cheetham, director of the Australian Personalised mRNA Cancer Immunotherapy Hub, hailed the vaccine as a "real breakthrough" in individualised medicine. "This is a final-stage study in a large population of people with melanoma that's really showing that this is outperforming the standard of care for treatment of these patients," he said. Still, experts have emphasized caution as the full results have not been released and it is not yet known precisely how much the vaccine reduced the risk of recurrence or spread. The trial is ongoing and participants will continue to be followed to determine its effect on overall survival.

There are, however, encouraging longer-term results from an earlier, mid-stage trial. Five-year data presented in June showed that adding the vaccine to Merck's immunotherapy drug Keytruda, an established treatment that helps the immune system fight cancer, cut the risk of the cancer returning by half. The combination also reduced the risk of it spreading to other parts of the body by 59 percent, compared with Keytruda alone. Moderna and Merck said they saw no new or increase in the rate of side effects from adding the vaccine to Keytruda.

The Merck and Moderna trial enlisted over 1,100 people who had melanoma removed by surgery. In an earlier phase trial, the drug showed 50% to 60% improvement in recurrence-free survival, metastasis-free survival and death, according to Dr. John Cooke, director of the Center for RNA Therapeutics at Houston Methodist. The companies said their Phase 3 results built on the previously reported successes. Moderna's CEO called the newly announced Phase 3 findings "a pivotal moment for the field of cancer research." "For many years, the idea of creating an mRNA treatment designed specifically for an individual patient's cancer was aspirational," the CEO said in a news release. "We are now helping turn that vision into a reality."

This is a treatment vaccine, not a preventive vaccine. It is designed for patients who already have cancer, and its aim is to stop the disease from coming back or spreading. The vaccine is also personalized: Each one is made based on the genetic characteristics of an individual patient's tumor. Doctors analyze a sample of a patient's tumor and use mRNA technology to target specific mutations within the cancer cells. A customized jab is then designed to teach the immune system to recognize and attack those cells. "Even the same types of cancer – for example, melanomas – can be very different," said Cheetham. "So, this (treatment) uses the genetic blueprint of each individual tumour to design a vaccine that will enable your body to recognise those tumour cells better and eradicate them from the body."

Despite being individually tailored, the vaccine can be produced within weeks. Each custom-made vaccine for the trial took six to eight weeks to develop. But the treatment still needs regulatory approval before it can be widely used. The drugmakers have said they would begin filings with regulators for approval. Cheetham believes it is realistic that the treatment could reach patients within the next two years. While experts believe the treatment would be expensive, there could be significant economic benefits. "Biological treatments are generally quite expensive. But the health economics of saving people's lives and reducing their hospital stays is also very powerful," said Brandon Wainwright, a professor at The University of Queensland's Institute for Molecular Bioscience. "From an economic point of view, this would be feasible for both companies and health systems."

Because the vaccine is designed around mutations in an individual tumor, doctors hope the same basic approach could be applied to other types of cancer. But not all cancers will necessarily respond equally well. Wainwright said one factor is how many genetic changes a tumor carries. Generally, cancers with more mutations provide more potential targets for a vaccine. Another is the tumor microenvironment – the cells and other material surrounding a tumor, some of which can suppress the immune response and make a cancer harder to attack. Trials are already under way in several other cancers. Cooke said researchers are exploring how they can develop mRNA-based therapies for bladder cancer, lung cancer and more. The Houston Methodist team previously developed a personalized mRNA vaccine to prevent recurrence of osteosarcoma, a rare and aggressive type of bone cancer.

Cooke said melanoma, which causes the most deaths among all types of skin cancer, was a good choice for the trial from Merck and Moderna. Melanoma is estimated to kill around 8,500 Americans this year. And Cooke said melanoma has a high risk of recurrence, often spreading to other parts of the body when it does return. Cooke said Keytruda (pembrolizumab) blocks a tumor's defense against T cells, part of our immune system. It essentially lowers the tumor's shield while the tailored mRNA vaccine rallies the body's T cells to recognize the tumor proteins as abnormal, attacking the cancer cells carrying them. He said RNA is like biological software, and scientists can code a vaccine to fight the unique characteristics of each patient's tumor. "This is going to give us another weapon in our armamentarium against cancer that looks very effective," Cooke said.

But accessibility and cost are challenges with such an individualized approach. Drugmakers operate big manufacturing plants to make vaccines at scale that are used by a lot of people, such as the annual flu shot. But Cooke said "distributed manufacturing" is likely needed to increase accessibility and hold down costs. That means smaller devices that can generate the personalized mRNA drug, perhaps in a hospital setting. "And that's going to happen," Cooke said. "That's going to happen in the next five years." Cooke said Merck and Moderna appear to be on their way to winning government approval for the new mRNA-based cancer therapy. That might happen within the next year or so, though he said regulators might want to see data from additional clinical trials first.