After years of unsuccessful attempts, the new mRNA antidote challenges melanoma and promises to attack even the toughest tumors: kidney, bladder and lung.
We tried to cure cancer with a vaccine long before mRNA became the magic word of medicine. And we failed. For decades, therapeutic vaccines have promised to teach the immune system to recognize tumors and defeat them, but they have encountered a long series of clinical failures, because cancer has proven to be a formidable opponent: it changes identity, hides, turns off our defenses. Today something seems to have changed, because for the first time in history a personalized mRNA vaccine, called Intismeran and built by Modern tailored to each individual patient, shown to be effective in a phase III study.
More than two years ago, in hospital rooms in 26 countries around the world, 1,137 patients with melanoma at high risk and who have already undergone surgery have agreed to experiment with a “tailored” therapy to try to avoid metastases and recurrences. «The preparation of the vaccine starts from the surgically removed tumor: its DNA is sequenced to identify the specific mutations of each individual melanoma, the so-called neoantigens that characterize the genetic profile of the tumor», he tells Panorama Giuseppe Curiglianoprofessor of medical oncology at the University of Milan and deputy scientific director of the IEO. «Subsequently, a bioinformatic algorithm identifies those most suitable for stimulating the immune system and builds a tailor-made mRNA vaccine for each patient, capable of coding up to 34 antigens. The objective is to educate the immune system to recognize these targets expressed on any micrometastatic cells and to eliminate them, reducing the risk of the tumor recurring.”
The genetic algorithm that arms the defenses against recidivism
The results of the study INTERpath.001 which the whole world is talking about today have achieved both objectives, survival free from recurrence and survival free from metastasis. But why do we call a vaccine something that does not prevent the disease, but cures it? “Vaccine is anything capable of activating an immune response directed against a specific target,” he explains Maria Rescignoordinary of general pathology of Humanitas University. «There are preventive ones and therapeutic ones. Here we are dealing with a therapeutic vaccine that serves for a sort of “sterilization” of the patient, trying to prevent those cells from giving rise to recurrence or metastasis. But we must also distinguish between personalized and universal therapeutic vaccines, i.e. ready to be used in all patients with the same pathology.”
For now, the transferability of the approach to the entire population is a complex issue. «In the case of Intismeran the preparation takes about six weeks. It can therefore work very well in the patient who has just undergone surgery and is free from visible disease. But for wider use we must reduce these times and make the technology more easily accessible”, concludes Rescigno.
The international experimentation that led to these results also has an Italian heart. And it brings with it one of the most fascinating and terrible paradoxes of clinical research: to know if a treatment works, those who administer it must accept that they don’t know if they are really using it. Paolo Asciertoprofessor of oncology at the Federico II University of Naples and one of the world’s leading experts on melanoma, experienced this paradox firsthand: in January 2024 he “enrolled” the first Italian patient to participate in the trial. In front of him was a therapy potentially capable of opening a new path in the fight against cancer. But also a question: was there really a vaccine or a placebo in that syringe? «INTerpath-001 is a randomized study and in double blindtherefore neither the patient nor the doctors know whether they are administering (and therefore receiving) the mRNA vaccine or the placebo”, Ascierto tells Panorama. «This obviously applies to all participants in the study. Obviously, as a doctor you would like to know immediately what you administered to your patient, but as a researcher you know that you don’t have to know, because that very rigor will allow tomorrow to establish with certainty whether the therapy really works. However, it was an exciting moment, because it meant bringing an experiment to Italy that we now know has given a positive result.”
The molecular identikit that guides the immune attack
Intismeran is not administered alone, but with the monoclonal antibody pembrolizumab. «The vaccine shows the immune system who it should attack, as if we were giving it mug shots of the enemy, helping it to recognize it more precisely and develop targeted T lymphocytes», continues Ascierto. «At the same time pembrolizumab removes one of the brakes that the tumor uses to prevent it from doing so. It is the strength of the combination: on the one hand we make the tumor more easily recognisable, on the other we give the immune system back the possibility of attacking it. We also try to create a immunological memoryso that those “photographs” remain over time and the system can eliminate any tumor cells that may reappear.” The professor, a motorbike enthusiast, does not give up a rider metaphor. «Today’s challenge is not only to make the immune system more powerful, but more precise. If immunotherapy removes the brakes, the vaccine tells him more precisely where to go and what to hit. We not only need a more powerful engine, but also brakes, good handlebars and above all to know where we want to go.”
The complete numerical data of the trial will be released at the end of October, during the congress ESMO of Madrid: for the moment it has only been communicated that the main objectives have been achieved. However, we know that in the previous phase II the vaccine had reduced the risk of recurrence or death by 49% and that of distant metastases by 59%.
Scientists reassure about any adverse effects. «Immunotherapeutics have been used for more than fifteen years now and we know that they are safe therapies», continues Curigliano. «Of course, they can cause side effects linked to excessive activation of the immune system and therefore adverse “friendly fire” events. For example thyroiditis, skin reactions and pneumonia; more rarely myocarditis. All problems are manageable and in most cases reversible. Even for therapeutic vaccines, the safety data will need to be carefully evaluated, but we are not starting from an unknown technology: we have long experience with this type of therapy.”
From neoantigens to cellular stress: the path towards universal vaccines
In addition to the melanoma trial, studies are underway on bladder, kidney and lung cancers. But the vaccines of the future will not live on mRNA alone: research is also focusing on other methods of target recognition, also to make these strategies potentially universal. This would lead to a collapse in research and production costs and therefore to greater sustainability of therapies. «The tumor cell is always very stressed, because it has to live with a very high number of mutations», continues Rescigno. «This stress causes it to expose particular “flags” on its surface, molecules that are characteristic of the state of stress. We are trying, with the 5 per thousand funds AIRCto identify these signals in order to build a peptide vaccine (which uses small fragments of tumor proteins) to teach the immune system to recognize and attack tumor cells. The vaccine has already been produced and we are awaiting authorization for clinical trials. It will be a phase 1, therefore a first trial on humans, above all to evaluate its tolerability and obtain the first efficacy data.”
After decades in which cancer was described as an invisible and inexorable enemy, medicine is trying to transform that same invisibility into a target. As Susan Sontag wrote way back in 1977, cancer will perhaps still remain “the disease that doesn’t knock before entering”. But now the challenge is to ensure that, after having managed to chase it out the front door with the weapons we already possess, we can better teach the immune system how to recognize it when it tries to return. To prevent it from harming us again.
