Cancer: the dream of a preventive vaccine takes shape

This article comes from the magazine Sciences et Avenir – La Recherche n ° 892 dated June 2021.

Prevent cancer from developing as soon as it appears, so you no longer have to fight it, as can be done with certain infectious diseases. This crazy dream that a handful of scientists would like to see come true consists of teaching the immune system to make antibodies and cells specializing in the detection and destruction of cancerous processes.

These tumors that form at random from genetic and environmental factors

There are, of course, already vaccines that prevent certain cancers, indirectly, by blocking so-called oncogenic viruses. But none that attacks the most frequent tumors, those that form at random from genetic, environmental (tobacco, alcohol, pollution, etc.) and hereditary factors. This is what teams from the Mayo Clinic in Rochester, Minnesota (United States) and the Cancer Institute at the University of Pittsburgh (United States) are trying to do, with a clinical trial started. in 2018 and still ongoing on 50 smokers or ex-smokers at very high risk of contracting lung cancer.

They received the so-called MUC1 vaccine, named after this protein normally expressed by epithelial cells – which form the inner and outer surfaces of many organs (lungs, stomach, intestines, eyes, etc.). “But in the event of a cancerous process, the MUC1 protein is overexpressed in an abnormal, mutated version. It is a marker present in numerous tumors (lung, pancreas, prostate, colon, etc.) which use it both as a engine of growth and defense against treatment “, explains Olivera Finn, professor emeritus at the University of Pittsburgh. It was his team that discovered this anomalous version of MUC1. With the idea of ​​making it a target tumor antigen for a true “vaccine, responsible for making the immune system produce the right antibodies. “The opportunities are incredible”, enthuses the one who has just left the director of the cancer immunology program at the American university.

It was in 2013 that his team unveiled this vaccine, the first of its kind, with the results of a first trial conducted this time on 39 elderly patients at risk of colon cancer due to advanced adenomas, a kind of premalignant tumor. Each had received three doses of the vaccine over a year. In all, 17 exhibited a strong protective response. The insufficient antibody production of the other 22 was attributed to an immune system already too weak to produce effective ones. “This suggests that it might be better to vaccinate people against colon cancer at an even earlier stage.”, explains Olivera Finn. Other pilot trials have since been conducted on prostate or breast cancer with stammering results. “The objective of these prophylactic vaccines [préventifs] is to strengthen the patient’s natural immune surveillance. If your doctor finds out that you have a high risk of cancer, the idea would be to vaccinate yourself to improve the immune system’s ability to contain abnormal cells and clear premalignant lesions instead of waiting to see if the cancer develops “, specifies the scientist.

Eliminate cancers at an early stage

Easier said than done, however. The idea is certainly not new. As early as 1943, the American oncologist Ludwik Gross demonstrated that mice from which tumors had been removed were protected against the reimplantation of tumor cells of the same lineage. In those in good health, on the contrary, the cancer developed very quickly. “These experiments proved that the immune system could recognize and eliminate cancers before they became clinically apparent, just as the smallpox vaccine could make the disease go away.”, comments Elizabeth Jaffee, professor of immuno-oncology at Johns-Hopkins University in Baltimore (United States).

However, unlike a foreign pathogen, well identified, tumors form complex cellular microenvironments, with cancerous elements, others not, and even healthy immune cells included … “The genes that change in the patient’s cells, just like the tumor antigens, are of extraordinary diversity. The great characteristic of cancer is its extreme lability”, recalls Pr Axel Kahn, geneticist, resigned president of the National League against cancer. “We are already unable to make a vaccine against HIV AIDS precisely because of the permanent evolution of its antigens, so cancer… But why not?”, adds the one who is mainly focused today on the arrival of messenger RNAs in immunotherapy.

In a review of the literature published in December 2020 on the development of MUC1 vaccines, researchers from Southwest Jiaotong University in Chengdu, China, reaffirm that MUC1 has “full potential to be used as a target for the development of a universal cancer vaccine”, highlighting, for example, its presence as a marker “in most human carcinomas”, which account for 90% of skin cancers. But long is the road: “MUC1 has been studied in immunotherapy for a long time now, and we have never really seen any dramatic benefit in patient mortality, so I don’t think it is a good candidate.”, says Fabrice André, director of research at the Gustave-Roussy regional center for the fight against cancer, in Villejuif (Val-de-Marne). “For a vaccine of this type, it would be necessary to know, in the face of a risk situation, what are the mechanisms of cancerization, identify the mutations at work and the antigens common to cancers in order to then vaccinate against them, precisely… but it is very difficult to anticipate these phenomena in a person who has not yet been affected by the disease “, continues the researcher. In other words, the “solution” MUC1, the only one tested in this sense to date, seems too simple. “But we could use other modern antigen modeling approaches associated with large epidemiological studies which would give the probability that a patient presents a particular antigen”, imagine Fabrice André to find better than MUC1.

A procedure that is not without risk

But the search for such a vaccine remains slow. First because treatment for patients is the priority, second because there are already ways to reduce your risk of cancer by taking care of your health and the environment. Finally, because the protocols for carrying out this research are complicated. Patients at risk, but healthy, should be followed closely over several years to assess vaccine efficacy; and above all, designating the wrong antigen for the immune system could also lead the latter to attack poorly identified non-cancerous cells. Cancer is always a kind of genetic derivative of the patient himself, and one should not induce an autoimmune disease in a healthy person on the pretext of avoiding him a hypothetical cancer. Today, therefore, it remains unlikely that a single vaccine could solve the scourge of cancer as simply as for a virus. Unless the MUC1 trial among ex-smokers in Pittsburgh is a pleasant surprise.

Towards personalized treatments

There is no single cancer: the disease is specific to each patient, with its own genetic characteristics, and therefore specific tumor antigens. A molecular diversity which contributes to the difficulty of developing a preventive vaccine. The solution could be found in personalized formulas. This avenue is currently being explored in a clinical trial launched at the start of the year in France at the Oncopole in Toulouse. Biotech Transgene has set up a platform using artificial intelligence to select tumor antigens specific to each patient before associating them with a viral vector responsible for educating the immune system to fight them. “The scientific and technological feat is to be able to do all the genetic analyzes and produce an individual vaccine in a few months according to the repertoire of mutations of each patient”, estimates Professor Jean-Pierre Delord who coordinates the clinical trial. If the formula helps treat the sick, it could also greatly reduce the risk of cancer recurrence. The first results of the tests which can be carried out on 30 patients should be known during the second half of this year.

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