Between expectation and prudence: what we know about the custom melanoma vaccine from Moderna and Merck

BarcelonaThe announcement by Moderna and Merck of a therapeutic vaccine to prevent metastasis of melanoma, the most aggressive skin cancer, arrived on Wednesday by surprise and sent the shares of these pharmaceutical giants soaring. In a joint statement, the two companies stated that they had obtained "positive results" in the phase 3 trial – the stage in which efficacy and safety in patients are reviewed before applying for marketing authorization for a drug. In the statement, they claimed to have achieved their two main objectives: relapse-free survival and distant metastasis-free survival – in other organs or lymph nodes – in patients who had already undergone complete tumor removal. But they did not provide any specific data on the vaccine. Nor is there, at the moment, an associated scientific publication.

The director of the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and head of the melanoma group at the same institution, Susana Puig, views the news positively. "Managing to include over 1,000 treated patients in multiple countries and centralizing the production of these vaccines is, from a logistical point of view, very interesting," she acknowledges. The fact that it is a phase 3 trial means that the research goes beyond an experiment with mice and is already in a fairly advanced process.

However, Puig calls for caution and points out that, at present, there are limitations in considering it a success. "We don't know if this vaccine benefits overall survival, what its costs will be, and if it will be implemented in Europe. It's one thing to present it to the Food and Drug Administration (FDA) and another to the European Medicines Agency (EMA)," she explains. Marisol Soengas, head of the melanoma group at the National Cancer Research Centre (CNIO), agrees. "In principle, these are very promising expectations, with caution, from a technologically very complex trial," she points out in statements to SMC Spain.

However, if it were approved in the United States, it could be a very important medical milestone: it would demonstrate that it is possible to manufacture a preventive therapy adapted to the mutations of each patient's tumor. In fact, it would become a precedent for oncological therapy based on messenger RNA technology, until now globally known for its role in containing the covid-19 pandemic.

According to its developers, intisomeran autogene – the name of the drug from Moderna and Merck – is a personalized therapeutic vaccine that is designed from each patient's individual tumor and uses messenger RNA to stimulate the immune system. The objective: for T lymphocytes to be able to recognize the tumor and attack a possible metastasis before it develops.

How would the vaccine work?

Greatly simplifying, this therapy adapts to the unique cancer mutations of each patient. First, a sample of the tumor must be obtained during surgery (or a biopsy) and then sequenced to identify specific alterations. The next phase is essential: by comparing tumor tissue with healthy tissue, using bioinformatics techniques, it is predicted which neoantigens – fragments of proteins generated by cancer, different from those in healthy cells – could be recognizable by the immune system. Once twenty to thirty are selected, messenger RNA sequences are designed to instruct the body to produce antigens that temporarily flag the cancer. Thus, the defenses learn to recognize the tumor as something harmful and neutralize it.

The production of this messenger RNA vaccine is similar to that of the COVID vaccine. A synthetic messenger RNA molecule is produced in the laboratory and encapsulated in lipid nanoparticles to protect it. It is then injected into the patient. If the immune system responds, T lymphocytes will be activated to attack tumor cells only if they reappear in another area of the body.

This entire process can take weeks. According to the two companies, it should be administered with an immunotherapy called Keytruda (pembrolizumab), which can deactivate the tumor's protection mechanisms and enhance the action of lymphocytes (what is known as an immune checkpoint inhibitor). This preventive treatment for metastasis would be directed solely at patients at very high risk of lymph node dissemination that can still be surgically removed and always in combination with immunotherapy. "It would not be useful for treating patients who already have metastasis and have already progressed to a first, second, or third line of treatment. It would be for people who we have already operated on and are disease-free," points out Puig.

Too soon to measure improvement

In December 2022, Moderna and Merck announced that, in clinical trials, the combination of the vaccine with Keytruda would have reduced the risk of relapse or death by 44%. In 2024, the companies presented updated data at the American Society of Clinical Oncology (ASCO) that would show a 49% reduction in the risk of relapse or death and a 62% reduction in the risk of distant metastasis or death compared to treatment with Keytruda alone. And more recently, this June, after five years of follow-up, data provided by the two pharmaceutical companies would indicate a 49% reduction in the risk of relapse or death and a 59% reduction in the risk of metastasis or death.

How have they looked at the vaccine's efficacy? By looking at how many treated patients relapse and how long it takes them to do so. "And it seems that when you add the vaccine, they relapse less or take much longer to develop metastasis. And that's what we know today," summarizes Puig. In fact, one of the criticisms of the announcement, according to the expert, is that an increase in survival is not demonstrated. "Before, with chemotherapy, the time until relapse could be extended from two to six months, but, in the end, the overall survival after three years was the same. Now, with immunotherapy, we achieve patients who remain relapse-free for a long time," he adds.

Yin Wu, a professional development researcher at the Wellcome Trust at King's College London, also believes it is still too early to know the extent to which this vaccine improves efficacy and at what cost it can be achieved compared to standard treatment. "Its importance will depend on the details published later," he tells SMC.

"The results will certainly be presented at a congress and published in a journal with detailed data – predicts Puig –. It is a very interesting approach because it adds practically no toxicity and individualizes treatment". In fact, in his opinion, the most interesting thing is that it would open up therapeutic alternatives. "With melanoma, 50% of patients benefit from immunotherapy, but with other tumors the percentage decreases. Perhaps with the vaccine more will benefit," he concludes.