During the COVID-19 pandemic, the potential – and real-world-impact – of mRNA-based vaccines attracted enormous public attention. November 9th 2020 marked a historic event, when BioNTech and Pfizer announced the success of Tozinameran (BNT162b2), the first ever mRNA vaccine, in a pivotal phase-III trial . Soon, it would become commonly known as the “Pfizer vaccine” or “BioNTech vaccine”. Just one week later, Moderna announced that their own vaccine, Elasomeran (mRNA-1273), had demonstrated a remarkable efficacy against symptomatic SARS-CoV-2 infection as well . As of early 2022, mRNA-based vaccines still represent the gold standard of SARS-CoV-2 vaccines in terms of efficacy against symptomatic and severe disease . Consequently, mRNA technology is heavily associated with the COVID-19 pandemic and many people are not aware that the foundation for its tremendous success was laid not by virology and infectious disease experts, but oncologic research.
This article provides a brief overview of the history of mRNA-based vaccines and outlines why they are being developed as new tools in the fight against cancer. It will be the first in a series of informative articles about mRNA technology, the rationale behind mRNA anti-cancer vaccines, and important ongoing clinical trials in the field.
Generations of researchers laid the groundwork
With the licensing of Tozinameran and Elasomeran by the EMA and FDA in December 2020, pharmaceutical products based on mRNA were approved for human use for the first time. Cancer vaccines based on the same technology are currently being studied in various indications in phase I and -II studies. However, these achievements were preceded by a series of scientific discoveries and innovations, without which the revolution that we are currently experiencing would not be possible. The initial idea of developing anti-cancer vaccines was based on the knowledge that the immune system plays a crucial role in fighting aberrant cells and that immune cells can recognize tumour cells via their mutated antigens. Secondly, the role and function of mRNA as a universal messenger molecule between genetic material and ribosomes, had to be elucidated. Thirdly, the technical basis for the introduction of artificial mRNAs and their expression in somatic cells had to be developed before the idea of injectable anti-cancer vaccines could be put into practice.
Figure 1: Timeline of notable events in the history of cancer immunotherapy and mRNA-based cancer vaccines.
The history of immunotherapy – an evolving and promising cancer treatment
The idea of fighting tumours by activating the immune system is considerably older than modern oncology. Attentive physicians were able to draw a connection between infections with high fever and spontaneous tumour remissions thousands of years ago . At the end of the 19th century, William Bradley Coley experimented with the pyrogenic bacteria Streptococcus pyogenes and Serratia marcescens, which he injected directly into the tumours of cancer patients, achieving long-lasting remissions in some cases . Cell-mediated immunity via cytotoxic T-cells has been shown to be particularly effective in combating tumour cells. Its upregulation is the goal of a new class of antitumour drugs, the checkpoint inhibitors, which reduce self-tolerance by inhibiting checkpoints in T-cell activation, thus increasing the antitumour activity of the immune system.
However, by reducing self-tolerance, many undesirable side effects may occur; accordingly, nonspecific immune activation is limited by its side effects.
Targets for mRNA anti-cancer vaccines
With the development of effective mRNA-based anti-cancer vaccines, it would be possible for the first time to direct the immune system against tumour-specific surface markers, the tumour-associated or tumour-specific antigens (TAAs or TSAs, respectively). Potentially, the immune response could be focused solely on tumour cells, which could lead to increased efficacy and tolerability compared to non-specific immunomodulators. Deep sequencing of tumour tissue can be used to identify tumour-specific neoantigens, which can then be targeted with tailored mRNA vaccines. Currently, patient-tailored mRNA vaccines by BioNTech and Moderna are under development , . While mRNA vaccines of one product line share one technological platform, each patient receives a personalized product. This has implications on the design of clinical trials, since traditionally, all patients in a given study arm receive the same treatment. Thus, mRNA vaccines potentially offer the first truly personalized option for cancer treatment.
Technological milestones in mRNA vaccine research
The role of mRNA as messenger molecule between genome and ribosome in all kingdoms of life was recognized from the late 1950s onwards . Soon, researchers realized the possibility of vaccinating organisms with exogenous mRNA, encoding a foreign antigen. mRNA is, however, extremely unstable, and rapidly degraded when injected directly into tissue, without any significant amount ever reaching the interior of a cell. At the same time, free RNA is a potent activator of the innate immune response . The use of a carrier matrix for transfection  and the modification of RNA with less immunogenic nucleic acids  made a decisive contribution to solving these problems. In the early 1990s, it was shown that inoculation of mice with packaged mRNA could elicit a specific cellular immune response . In the year 2000, CureVac was founded, the first company whose expressed goal was to develop mRNA vaccines to fight cancer. The currently most successful companies in the field of mRNA vaccines, BioNTech and Moderna, were founded in 2008 and 2010, respectively, also with the goal of developing anti-cancer vaccines.
Currently, different mRNA anti-cancer vaccines are being investigated in a number of clinical trials, mostly phase I and phase II. Some studies test vaccines that are directed against TAAs or TSAs. Other studies are designed to investigate highly personalized, tumour-specific vaccines. Commercial enterprises and academic institutions alike are involved in the development of these anti-cancer vaccines, often targeting types of cancer that are difficult to treat, e.g., melanoma or glioblastoma.
Conclusion and outlook
Immuno-oncology is not a completely new discipline, but for decades it has eked out a niche existence in the shadow of radiotherapy and chemotherapy. Only in recent years, with the advent of antibody therapies and checkpoint inhibitors, has it received increasing attention. Thanks to the technological revolution in the field of mRNA-based vaccines, it could soon experience a leap in importance. It undoubtedly has the potential to become an important component in the fight against cancer. We will follow the current and future developments with great interest and look forward to the coming revolution.
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Author: Sven Vanselow
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