For years they have been awaited as a possible revolution in the fight against tumors, and now personalized mRNA vaccines have reached an important milestone. On October 24, at the European Society of Medical Oncology (Esmo) congress in Madrid, detailed results of the first large phase 3 trial of one of these melanoma therapies were presented: the treatment reduced the risk of recurrence or death in operated patients by 42 percent, when added to standard immunotherapy. A promising result, however welcomed with cautious enthusiasm – if not open skepticism – both by part of the scientific community and by the world of finance, which in recent months had placed a lot of focus on the new pharmaceutical blockbuster from Merck and Moderna (the two companies that came to the fore during the pandemic with their mRna anti-Covid vaccines).
The melanoma vaccine
The therapy developed in tandem by the two pharmaceutical companies is called autogenous intismeran, and uses the same messenger RNA platform used against Covid-19, but adapting it to the world of oncology. The idea behind it is simple, although the technology needed to implement it is complex: each tumor has a combination of unique genetic mutations that can make it recognizable to the body’s defenses, and a vaccine can exploit these genetic differences, teaching immune cells to identify tumor cells that may be left in the body after surgery.
Messenger RNA is then tailor-made to carry instructions into patients’ cells to make the tumor proteins, called neoantigens, that characterize their tumor. The immune system thus learns to recognize those targets and attack the cells that present them. It is therefore not a preventive vaccination, but a form of hyper-personalized therapeutic immunotherapy.
How it is produced and who it is intended for
To prepare the vaccine it is necessary to start from the tumor removed during the operation. Its genetic material is analyzed to identify the most promising mutations, those that can help the immune system distinguish diseased cells from healthy ones. Based on this analysis, an mRNA sequence is constructed which contains the instructions to produce up to 34 neoantigens.
The therapy is designed for people with high-risk skin melanoma who have already undergone surgery. It is administered together with pembrolizumab, an immunotherapy drug already used against various tumors, which works by removing one of the molecular mechanisms used by cancer to slow down the immune defenses. The two strategies therefore work in a complementary way: the drug enhances the immune response, and the therapeutic vaccine provides the immune system with targets to hit.
The results: fewer recurrences and metastases
On paper the strategy seems simple and promising, but obviously it must be evaluated in the light of facts. This is why the results just presented in Madrid were awaited with great interest. The INTerpath-001 study is a phase 3 trial (the last before the marketing of a therapy), which involved 1,137 patients with melanoma who underwent surgery to remove the tumor. Participants were divided into two groups: one received the personalized vaccine together with pembrolizumab, the other the immunotherapy drug alone.
After a median follow-up of about two years, the combination reduced the risk of relapse or death by 42 percent compared to immunotherapy alone. At two years, 82.2 percent of patients treated with both drugs were alive and without relapses, versus 70 percent of those who received pembrolizumab alone. Positive results, because they show an additional benefit compared to an already consolidated therapy, which however do not yet demonstrate that the vaccine makes people live longer: the data on overall survival are still insufficient to establish a statistically significant difference.
Wall Street reacts badly
Despite the success in the trial, the new anti-cancer vaccine appears to be limping on the stock market for now. On October 22, before the official presentation of the results, a leak revealed the results of the study causing a collapse in the shares of Moderna and Merck. The reason is simple: after months of strong increases, expectations on the commercial potential of the vaccine had become very high, and for an innovative, expensive and complex therapy from a logistical and technological point of view such as autogenous intismeran, truly stellar clinical results were needed to confirm investor confidence.
The trial results did not live up to similar expectations. The effectiveness is high, but not a revolution. And if reducing the risk of recurrence is a clinically significant result, the main objective is obviously to cure the tumor or at least to concretely extend patients’ life expectancy. However, it will take years to understand whether the new therapy produces a real increase in survival. Furthermore, not all patients respond in the same way: identifying the right mutations and predicting which ones will be effectively recognized by the immune defenses remains a challenge, and in the trial 17 percent of the patients initially recruited were excluded from the study because the samples taken from the tumor did not allow the finding of neoantigens.
A revolution yet to be demonstrated
As an article by Sciencethe real effectiveness of vaccination with neoantigens is, moreover, still to be demonstrated, because in the past even vaccines against Covid-19 have shown that they can enhance the effects of immunotherapy, and therefore it could be the mRNA (and not the antigens contained in the vaccine) or the lipid nanoparticles that carry it that are truly responsible for reducing the risk of relapses. That’s not all: at this year’s Esmo congress, other strategies were presented, such as the use of neoadjuvant immunotherapy (i.e. administered before surgery), which seem to promise comparable efficacy to the Merck and Moderna vaccine, at a much lower price.
In short, the scientific success is undeniable. But the real revolution will depend on the ability to transform these results into lasting, accessible and replicable benefits in clinical practice. And this, for now, is still to be demonstrated.