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Jacqueline Mann
In December 2020, less than a year after the COVID-19 pandemic was declared, the Food and Drug Administration (FDA) granted emergency use authorization for the Pfizer-BioNTech and Moderna vaccines to prevent COVID-19. These vaccines work differently from traditional immunizations: they contain a specific sequence of messenger RNA (mRNA) that tells the recipient’s cells to manufacture a protein found on the surface of SARS-CoV-2. This spike protein doesn’t function like a full virus, but it does teach the immune system what the virus looks like so that it can respond in the future.
While this development was widely celebrated, the unusually rapid timeline and unfamiliar technology fueled vaccine hesitancy for many. Indeed, mRNA vaccines for COVID-19 came to market remarkably quickly, but they did so following decades of research that had already established a platform poised for adaptation and scaling. Additionally, many of the technological advancements that made the COVID-19 mRNA vaccines so successful were initially developed in the context of cancer vaccines.
While the Pfizer-BioNTech COVID-19 vaccine was the first to earn FDA approval, the concept of mRNA vaccines was actually introduced in the early 1990s, with the first preclinical study, which targeted a cancer-associated protein, published in 1995. Later studies tested modifications to mRNA molecules to improve stability, enhance protein production, and minimize undesirable immune responses. Others optimized various delivery systems, including the lipid nanoparticles used as carriers in the COVID-19 mRNA vaccines. Furthermore, numerous safety advantages of mRNA were noted, such as its inability to integrate into the recipient’s genome like DNA might.
As previously discussed on OncoBites, many cancer vaccines differ from those for infectious diseases in that they aim to treat an existing illness rather than prevent it. Cancer vaccines often work by introducing specific proteins expressed by cancer cells (“antigens”). mRNA sequences can be designed to encode any protein antigens, which will be translated upon delivery. The proteins are then used to train the immune system to recognize and attack other cells in the body expressing those antigens.
Because each tumor is unique, deciding which antigens to target in the context of a specific cancer subtype- or even an individual patient- presents a major challenge. Fortunately, mRNA is especially well-suited to address this issue. Because mRNA can be easily and rapidly synthesized to encode virtually any peptide sequence, highly personalized vaccines can be generated to target a patient’s unique disease in a matter of weeks. An early trial tested these individualized mRNA vaccines in patients with histories of recurrent melanoma. After vaccination, all patients developed immune responses directed against a percentage of the intended neoantigens, and researchers observed a significant reduction in cumulative metastatic events in the 24 months following vaccination. Three of five patients with progressing tumors at the start of vaccination exhibited objective clinical responses. While these results are promising, more research is needed to optimize these protocols and understand treatment failures.
Other studies have used vaccines combining mRNAs encoding the most common antigens observed in certain tumors, such as melanoma and head and neck cancer. This strategy might not serve patients with uncommon antigen/neoantigen profiles but does mitigate the delay and expense of analyzing individual tumors. Still, more trials are testing mRNA cancer vaccines paired with other immunotherapy modalities, such as immune checkpoint inhibitors and costimulatory signals or cytokines, which might aid in activating an even more robust anti-tumor response.
Although the development of mRNA-based COVID-19 vaccines was heavily informed by decades of research on cancer vaccines, there are currently no FDA-approved mRNA vaccines for cancer or any other disease. Researchers are only just beginning to tap into the potential of mRNA, however, and COVID-19 vaccines have now demonstrated on a massive scale that mRNA vaccines can indeed be safe and efficacious. This success has surely reinvigorated investigators’ enthusiasm for mRNA vaccines and bodes well for future investment in therapeutic cancer vaccines!
Edited by Jessica Desamero
OncoBites 
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