More than 300,000 new cancers are diagnosed in France each year, with over 150,000 deaths attributable to them. Although clinical research has made significant progress over the last few decades, enabling more accurate diagnosis, better treatment and even a cure for certain types of tumours, the need for new therapies remains immense. Molecular biology has shown that cancers are caused by an accumulation of alterations in the genome of cells throughout life, which in the long term can lead to uncontrolled cell proliferation. But malignant tumours use other strategies to spread. For example, they modify their ‘microenvironment’ in order to build a new network of small blood vessels around them, providing them with the nutrients they need. This ‘neovascularisation’ has another effect: it protects the tumours from the immune system by creating a kind of shield. The effective immune response is thus weakened, and the body begins to tolerate the tumour.
The immunostimulatory properties of synthetic messenger RNA (mRNA) can help to correct this phenomenon. This strategy consists of producing mRNAs coding for proteins considered foreign to the normal patient, known as “tumour epitopes”. These molecules can be considered as immune biomarkers of tumours. When the immune system recognises these proteins, it reacts almost as it would to pathogens (viruses or microbes), keeping these markers in memory. This is why these mRNAs are described as cancer vaccines. By injecting patients with these vaccines, the aim is not to vaccinate against a pathogen, but to retrain the immune system to recognise one or more markers of cancer cells. The specific marker, or markers, still need to be identified.
A complex task, but not an impossible one
Cancers use multiple pathways to develop and have great plasticity. It is therefore crucial to study the genome of each patient’s tumour to identify relevant tumour epitopes. From a medical point of view, these tailor-made therapies are interesting, but the prototypes are likely to be very expensive and will be reserved for patients treated in centres with expertise in immunotherapy, since their implementation is so technical.
To simplify the field of investigation, biomedical companies are considering the production of mRNAs targeting common and well-known tumour antigens. The German company BioNTech, which became known for having developed the anti-Covid vaccine with Pfizer, is leading the way in these programmes. It already has several mRNA candidates that have been studied in haematological tumours as well as in numerous solid tumours.
Among the tumour antigen epitopes, some are common to cancers occurring in different organs. This is the case, for example, of certain membrane receptors such as EGFR (HER1) or HER (2, 3 or 4), which are present and often activated (by different molecular mechanisms) in many adenocarcinomas, i.e. in subgroups of breast, prostate, thyroid, pancreatic, ovarian, kidney, liver and colorectal cancers. However, in advanced tumours, other oncogenes are activated.
A market launch in the near future?
Most of these vaccine candidates are currently in Phase 1 or 2 clinical trials, testing their safety and efficacy against metastatic melanoma, head and neck cancer, ovarian tumours, and colorectal cancers. While it is usual to do a phase‑3 study comparing the vaccine to previous “standard” treatments before applying for marketing authorisation, in the case of these vaccines this may not be possible. It is indeed ethically questionable to construct a clinical trial where some patients are treated with a conventional chemotherapy empirically developed in the clinic on the basis of a response rate and duration of response. Frequently used conventional chemotherapies act by impairing cellular functions, for example by preventing DNA repair, or by blocking the mitotic spindle, but resistance to these mechanisms is only beginning to be elucidated.
In the context of advanced tumours with multiple alterations, it may also be very complex to construct groups for comparison, i.e. with patients sharing exactly the same molecular abnormalities in the active and control arms. These innovations could therefore potentially reach the market on the basis of strong phase‑2 data.
Ultimately, advanced tumours are highly heterogeneous and at the same time highly plastic. When they spread throughout the body, forming metastases, despite the administration of one or more treatments, the ‘persistent’ tumour cells are remarkable for their adaptability and for the presence of many defects that prevent them from dying. In this situation, it is commonly accepted that the cancer will need to be targeted by multiple approaches in combination. A very large number of laboratories are interested in RNAs for future cancer treatments. If successfully developed, they will complement the current therapeutic arsenal, combining with other targeted therapies to further reduce mortality rates for these diseases.