Local time: August 19 — Merck announced phase 3 trial results for its joint therapy with Moderna in high-risk IIB–IV melanoma patients. The treatment significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) for nearly 800 participants in the trial group. The study included 1,137 patients with malignant melanoma, two-thirds of whom received the experimental therapy and the remainder served as controls.

Once the results were announced, Moderna's stock price more than doubled and Merck's shares reached an all-time high. The therapy centers on two key components: pembrolizumab (KEYTRUDA), the cornerstone of current advanced cancer treatment, and the mRNA cancer vaccine Intismeran Autogene—the most critical variable—also known as mRNA-4157 and V940.

First-line Cancer Treatment

In the human body, some cancer cells are extremely hard to eliminate. They disguise themselves as normal cells, grow gradually, and metastasize, eventually leading to death. Immunologists James P. Allison and Tasuku Honjo won the 2018 Nobel Prize in Physiology or Medicine for discovering how cancer cells conceal themselves. One method of disguise involves PD-L1 proteins on the surface of cancer cells binding to PD-1 receptors on T cells, sending a "I am harmless" signal that stops T cells from attacking them.

Merck developed K drug using this mechanism. K drug exhibits much higher affinity for PD-1 receptors than for the PD-L1 protein, with very strong binding that restores T cell attack on cancer cells.

As a groundbreaking cancer immunotherapy, K drug received FDA approval for melanoma treatment in 2014 and has since expanded to treat at least 15 cancer types. Scientists have also achieved promising results by combining it with chemotherapy and other therapies.

In melanoma treatment, Drug K treats unresectable or metastatic (advanced) melanoma and serves as adjuvant therapy after tumor resection to reduce recurrence risk. In today's trial, patients had high-risk Stage IIB-IV melanoma with large tumors, ulceration, spread to nearby lymph nodes or skin (Stage III), or distant metastasis to skin or other organs (Stage IV).

Several years ago, Merck conducted multiple studies showing that after resection of high-risk Stage III melanoma, 1-year K drug treatment reduced the risk of tumor recurrence and death by approximately 43% within 1.5 years. This benefit persisted for at least 3 years. The treatment also demonstrated similar effects in Stage II melanoma, lowering the risk of recurrence or death by about 38% within 3 years and reducing the risk of distant metastasis or death by approximately 41%.

More excitingly, according to Merck's official website data, adding the mRNA cancer vaccine mRNA-4157 to K drug treatment further reduces the risk of tumor recurrence or death by 49% and the risk of distant metastasis or death by 59%. The most common adverse events include fatigue, injection site pain, colitis, and myalgia.

However, the two companies have not yet released specific trial patient data or disclosed average patient survival times. More details will be announced at medical conferences later this year.

Key Variable

According to a 2022 study published in Nature Biotechnology, the cancer vaccine mRNA-4157 primarily consists of an artificially synthesized mRNA strand encoding up to 34 neoantigens targeting melanoma. This mRNA strand is encapsulated in lipid nanoparticles (LNPs) and delivered via intramuscular injection.

Once inside the body, mRNA is taken up by cells, translated into protein, and displayed to immune cells. As these tumor-specific antigens are recognized, the body's anti-cancer immune response is fully activated. Immune cells then patrol the body to detect and eliminate microscopic residual disease not removed during surgery or escaped cancer cells. This process may also enable the immune system to develop long-term memory, offering protection for over a decade—a significant breakthrough in the quest to cure cancer.

As early as 1990, scientists discovered that mRNA encoding antigen proteins could be used to make vaccines. However, it wasn't until several years ago that the development and mass production of COVID-19 mRNA vaccines finally overcame technical hurdles related to mRNA stability and delivery. This breakthrough propelled mRNA cancer vaccines to the forefront of cancer vaccine research and development. Yet, a new challenge emerged: how to identify tumor-specific neoantigens?

Compared to viruses, cancer antigens are more complex. As described in a January article in Global Science magazine, tumors in patients' bodies evolve rapidly, continuously dividing and proliferating abnormally while accumulating numerous mutations. These mutated abnormal proteins or their fragments are known as neoantigens. Because of varying physiological environments within the human body, cancer cell neoantigens differ from person to person.

For each cancer patient, researchers must identify which tumor neoantigens will persist and which can most effectively trigger immune recognition and activation.

Some studies indicate that mutations common in most tumor cells may not elicit reliable immune responses. Conversely, mutations that do not drive cancer development can actually enable the immune system to recognize tumors. These factors complicate neoantigen discovery.

To put it in perspective, this is like finding over 1,000 specific glass beads from Plate A among tens of thousands of beads across Plates A and B, then selecting dozens that meet the criteria. The workload is immense—and identifying neoantigens for vaccine development is even more complex.

After surgically resecting tumor samples from patients, teams must race against time to identify dozens of neoantigens and administer the developed vaccine before cancer recurrence. Since newly emerging tumors may harbor new mutations, the vaccine could become ineffective.

The entire screening process is highly complex, closely mimicking the human body's natural mechanism: tumor antigens are recognized and processed by immune cells, then presented to T cells to trigger an immune response.

Researchers break this process into multiple steps: confirming whether neoantigens are processed within cancer cells, presented on their surface, recognized and processed by immune cells, further presented to T cells, and finally distinguished by T cells as cancer cell antigens. Ultimately, scientists identify dozens of the most promising candidate neoantigens.

In 2023, Moderna's Head of Tumor and Therapeutic Development, Kyle Holen, published a blog post. He noted that customizing anti-melanoma vaccines for each patient is challenging—not only due to the complexity of drug design but also because of the need to optimize production plans and resources to ensure timely administration.

At that time, they had already begun using AI to process thousands of patient samples. A suite of fully integrated AI algorithms extracted next-generation sequencing data from patient tumor and blood samples, analyzed gene mutations, and predicted up to 34 neoantigens most likely to trigger immune responses.

Additionally, he stated that this algorithm will integrate clinical and immunogenicity data to continuously improve over time, enabling more effective screening of neoantigens with the highest clinical activity.

In this 3-phase clinical trial, each patient received an injection of a personalized mRNA-4157 vaccine derived from their own resected tumor tissue. The vaccine contained long mRNA chains encoding up to 34 neoantigens. Throughout treatment, patients were administered vaccine injections every 3 weeks alongside K-drug therapy (400 mg every 6 weeks, for up to 9 cycles, over approximately 1 year).

To scale vaccine production for a "one person, one drug" approach serving thousands and ensure timely delivery of mRNA-4157 vaccines, Holen also highlighted that Merck developed Maestro, an end-to-end AI scheduling algorithm for downstream vaccine manufacturing. Moderna leverages this to tightly coordinate clinical operations, production, quality assurance, and transportation logistics, automatically adjusting downstream plans in response to any changes to guarantee each dose of mRNA-4157 vaccine reaches every patient on time.

Promising Future

mRNA cancer vaccines may first achieve breakthroughs in melanoma, a result closely tied to the high mutability of these tumors, which readily generate neoantigens. However, these vaccines can also be effective in tumors with fewer neoantigens, such as pancreatic cancer.

According to The Wall Street Journal, in April this year, BioNTech and Genentech jointly developed personalized mRNA vaccines for pancreatic cancer patients that showed promising results: in the trial, half (8 patients) responded to the vaccine, and 6 survived more than 6 years—typically, only about 1/8 of pancreatic cancer patients live 5 years or longer after diagnosis. Global Science magazine detailed this story in an article published earlier this year.

The report highlights a patient who received the vaccine. She was already 76 years old, and initially, only about 1 in 500,000 of her immune cells could recognize the tumor. After completing the fourth vaccine dose, the proportion of her most prevalent anti-tumor T cells rose to 1/20–1/50, representing an increase of more than 20,000-fold. Additional trials targeting other cancers are also underway. Currently, Moderna and Merck are collaborating on at least 8 Phase 2 or 3 clinical trials, primarily focusing on non-small cell lung cancer, bladder cancer, and renal cell carcinoma.

According to a July review in the Journal of Translational Medicine, neoantigens are critical for the clinical success of personalized cancer vaccines. Today, AI leverages high-throughput sequencing, immunopeptidomics, and deep learning models to guide neoantigen discovery and deliver clinical value. However, because neoantigen discovery remains highly complex, more professional data is needed to train AI in screening for neoantigens with true immunological relevance.

On the other hand, researchers are continuously quantifying gene mutations across various tumors and identifying the neoantigens they express. For example, in the study above, the authors analyzed the Cancer Genome Atlas (TCGA) database and identified 933,954 neoantigens from nearly 900,000 somatic mutations across 20 different solid tumor types. These discoveries form the foundation for developing future mRNA cancer vaccines.

The study also found that certain neoantigens are expressed in at least 5% of patients across different cancer types or within the same cancer. Additionally, some studies are exploring an alternative mRNA cancer vaccine strategy—targeting shared neoantigens by developing vaccines against common mutations to simultaneously treat thousands of patients.

Today, we've reached a new milestone in cancer treatment. Building on immunotherapy, we've introduced personalized mRNA cancer vaccines. As research and trials advance, we may soon answer key questions: Can many tumors be cured? Can early immune surveillance be established while tumors are still developing to prevent cancer onset?

Reference links:

Global Science magazine January 2026 issue article "Cancer Vaccine Enters Customization Era"

https://pubmed.ncbi.nlm.nih.gov/32946353/

https://ascopubs.org/doi/10.1200/JCO.23.02355

https://www.modernatx.com/en-US/media-center/all-media/blogs/advancing-fight-against-cancer

https://www.nature.com/articles/s41587-022-01294-2

https://www.wsj.com/health/pharma/moderna-merck-vaccine-succeeds-in-preventing-melanoma-from-returning-540e9e18

https://www.wsj.com/health/healthcare/new-drugs-for-pancreatic-cancer-show-remarkable-promise-for-deadly-disease-b4e1b504

https://www.modernatx.com/research/product-pipeline