Between expectation and prudence: what do we know about the personalized vaccine against melanoma

BarcelonaThe announcement by Moderna and MSD 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 note, the companies stated that they had obtained "positive results" in the phase 3 trial – the stage in which efficacy and safety are reviewed in patients before applying for marketing authorization –. In the statement, they claimed to have achieved 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.

"It is extraordinarily hopeful news, but we have to wait to see the complete data. And, above all, it remains to be seen what the overall survival will be. The same study will continue precisely to evaluate it," explains Eva Muñoz-Couselo, head of the Melanoma and Other Cutaneous Tumors Group at the Vall d'Hebron Institute of Oncology (VHIO). Susana Puig, director of the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) and head of the melanoma group at the same institution, also positively assesses the news. "Achieving the inclusion of more than 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 this time, 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 is one thing to present it to the Food and Drug Administration (FDA) and another to the European Medicines Agency (EMA)," she states.

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 is a personalized therapeutic vaccine that is designed from each patient's individual tumor and uses messenger RNA to stimulate the immune system. The goal: that T lymphocytes can recognize the tumor and attack a possible metastasis before it develops. "What is especially important now is that this biological sophistication has not remained just an attractive laboratory idea: for the first time it has produced a positive result in a phase 3 trial," argues Muñoz-Couselo.

How would the vaccine work?

Very simplified, this therapy adapts to the unique cancer mutations of each patient. First, a tumor sample 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 recognized 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.

The manufacturing of this messenger RNA vaccine is done in the laboratory. A synthetic messenger RNA molecule is created 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 the tumor should it reappear.

According to the two companies, the vaccine should be administered with an immunotherapy called Keytruda (pembrolizumab), which can deactivate the tumor's protective mechanisms and enhance the action of lymphocytes (what is known as an immune checkpoint inhibitor). Until now, cancer vaccines attempted to direct the immune system against one or several antigens shared by many tumors and, therefore, administered the same vaccine to different patients. "Here the approach is completely different: each vaccine is unique and is not used in isolation, but in combination with immunotherapy. While the vaccine attempts to generate and expand a specific immune response against the tumor, pembrolizumab removes one of the brakes that the tumor uses to inhibit this response," summarizes Muñoz-Couselo.

Too soon to quantify the improvement

In December 2022, Moderna and MSD announced that, in clinical trials, the combination of the vaccine with Keytruda had 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 metastasis or death compared to treatment with Keytruda alone. And this June, after five years of follow-up, data provided by the pharmaceutical companies indicated a 49% reduction in the risk of relapse or death and a 59% reduction in the risk of metastasis or death. "This is very relevant because the vaccine has not been compared against a placebo or against the absence of treatment, but against pembrolizumab," states Muñoz-Couselo.

Catalonia has participated in this study and one of the centers has been precisely Vall d’Hebron, which has actively included patients, although there were also other centers at the state level in Madrid, Malaga and Valencia. Preventive metastasis treatment is aimed 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.

How was the vaccine's efficacy assessed? 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 longer to develop metastasis," summarizes Puig. In fact, one of the criticisms made by the expert is that an increase in survival is not demonstrated. And to claim that it will change the standard of treatment is still too soon.

"We need to know the real magnitude of the benefit, the detailed safety, overall survival, and finally, that regulatory agencies evaluate all this data. Therefore, it can be a turning point for the field, but we should not yet present it as a new standard of treatment," warns Muñoz-Couselo. Puig agrees, considering that the most interesting aspect is that therapeutic alternatives would be opened up. "With melanoma, 50% of patients benefit from immunotherapy, but with other tumors the percentage decreases. Perhaps with the vaccine more benefit," he concludes.