mRNA Vaccine Shows Lasting Protection Against Melanoma

A personalized mRNA-based cancer vaccine, developed by Moderna in collaboration with Merck, has demonstrated sustained protection against melanoma recurrence over a five-year follow-up period, according to results presented Monday at the American Society of Clinical Oncology (ASCO) annual meeting and simultaneously published in the Journal of Clinical Oncology. The findings represent the longest follow-up data yet for a personalized mRNA cancer vaccine and mark a significant milestone in the field of cancer immunotherapy.

A Landmark Clinical Trial

The Phase 2b KEYNOTE-942/mRNA-4157-P201 trial enrolled 157 patients with high-risk Stage III/IV melanoma who had undergone complete surgical resection. Patients were randomized in a 2:1 ratio to receive either the personalized mRNA vaccine — known as intismeran autogene (mRNA-4157/V940) — in combination with Merck’s immunotherapy drug Keytruda (pembrolizumab), or Keytruda alone.

According to NPR, after five years of follow-up, 68.8% of patients who received the combination therapy remained cancer-free, compared with 49.1% of those who received Keytruda alone — representing a 49% reduction in the risk of recurrence or death. The combination also cut the risk of cancer metastasizing by nearly 60%.

Overall survival rates were equally striking: 92% of combination therapy patients were alive at five years, versus 71% in the control group.

How the Personalized Vaccine Works

Unlike the COVID-19 mRNA vaccines, which delivered the same genetic instructions to everyone, this approach is tailored to each individual patient’s cancer. Scientists sequence a patient’s tumor to identify up to 34 unique molecular fingerprints called neoantigens, which are then encoded into a custom mRNA vaccine.

“The COVID vaccine was the same RNA fragment given to everybody,” Dr. Sarah Arron, a dermatologist and skin cancer surgeon not involved in the research, told NBC News. “Whereas in this case, the antigen itself is not one virus, it’s [each] patient’s tumor.”

When injected, the vaccine trains T cells to recognize and attack cells displaying those specific neoantigens. Keytruda works alongside it by blocking PD-1 receptors on T cells, preventing cancer cells from hiding from the immune system.

“It’s training the immune system to recognize the tumor signature long after the tumor is gone,” said Jeff Coller, a professor of RNA biology and therapeutics at Johns Hopkins University who was not involved in the trial.

Expert Reactions

Dr. Janice Mehnert, a melanoma specialist at NYU Langone Health and senior author of the study, called the results compelling. “I think this is strong evidence that this therapy, when used in combination with immunotherapy, can demonstrably reduce the risk of dying from this disease,” she said.

Dr. Shailender Bhatia, director of the melanoma team at Fred Hutch Cancer Center, said that if the ongoing Phase 3 trial yields similar results, it “will be paradigm-shifting.” He added: “We have tried to use vaccines in cancer therapy for decades, but the efficacy has not been clinically relevant in phase 3 trials to date. If this is successful, this will open up a new field.”

Safety and Next Steps

Side effects were mild and consistent with previous reports — fatigue, injection site pain, chills, and flu-like symptoms lasting a few days. No new safety signals emerged over the five-year period.

A larger Phase 3 trial (INTerpath-001) with nearly 1,000 patients is fully enrolled, with results expected in the coming months. If positive, Moderna and Merck plan to seek FDA approval. The companies also have eight additional Phase 2 and Phase 3 trials underway testing mRNA vaccines against other cancers, including non-small cell lung cancer, bladder cancer, and renal cell carcinoma.

For Connie Franciosi, an 80-year-old trial participant who received the combination therapy after being diagnosed with late-stage melanoma in 2020, the results speak for themselves. “I am cancer-free,” she said. “Life is good.”

Looking Ahead

The findings represent a critical proof of concept for personalized mRNA cancer vaccines — an approach that has been in development for nearly two decades but had not previously demonstrated such durable results. According to the National Cancer Institute, approximately 112,000 new cases of melanoma are diagnosed in the U.S. each year, and in about half of high-risk patients, the disease returns within five years.

While challenges remain — including manufacturing complexity, cost, and ensuring equitable access — the five-year data provide the strongest evidence yet that personalized mRNA vaccines could transform the treatment landscape for melanoma and potentially many other cancers.