By Stephan Isringhausen, Senior Analyst and Holger Müller, Vice President
The swift development, good safety profile, and efficacy outperformance of mRNA-based COVID-19 vaccines led to broad clinical adoption and highlighted the significant potential of mRNA technologies
Considerable expansion of development projects and deal activity around mRNA vaccine technologies demonstrates stakeholder awareness and interest
In addition to infectious diseases, several other use cases for mRNA vaccines have emerged. With a growing pipeline in early-stage assets, mRNA vaccines in oncology hold great hope and potential
Current clinical evidence suggest that mRNA vaccine monotherapies are not yet available to deliver the desired efficacy, but checkpoint inhibitor-based combination therapies are an area to monitor closely
Messenger RNA, or mRNA, plays an indispensable role in human biology by transferring genomic information stored as DNA within our cell nucleus to make the proteins required in every living cell. To provide a dynamic, continuous, and ‘on demand’ protein production for cells, most mRNAs are expressed transiently and have a short half-life.
mRNA vaccines work by artificially introducing mRNA strands into cells that trigger the intracellular production of a specific target protein. These target proteins – or fractions of proteins – are typically surface proteins that specify the cells as antigens, triggering an immune response against that target protein. Importantly, the mRNA vaccine is not the drug itself, but the recipe for a protein that triggers an immune reaction.
mRNA Vaccines Have the Industry’s Attention
Following the leap from novel pipeline approach to game changer in fighting a global pandemic within a year, the pipeline of mRNA vaccines has experienced tremendous growth in recent years (Figure 1). Despite this growth, mRNA vaccine pipeline assets are still dominated by first mover and early innovators Moderna, CureVac, and BioNTech, who account for more than 50% of all advanced mRNA vaccine pipeline assets.
Figure 1: Development of mRNA Vaccine Pipeline by Stage and Year, and Pharmaceutical Companies with Advanced Pipeline
In addition, Big Pharma has brought the technology to the attention of a wider group of developers through a string of licensing deals and outright acquisitions. Although mRNA technology is principally agnostic to the therapeutic area, it is not surprising that Big Pharma with prior experience in the vaccine space, like Pfizer, Sanofi, Merck, and GSK, have shown particular interest in the mRNA space (Figure 2).
Figure 2: Selected mRNA Vaccine Partnerships and Acquisitions by Big Pharma
mRNA Vaccines Can Be Applied to Oncology Applications
Beyond the now self-evident application of mRNA vaccines in infectious diseases, excitement has been reignited to leverage the mRNA mechanism of expressing specific surface proteins in oncological applications. Instead of the viral spike protein, mRNA oncology vaccines will express tumor-specific surface proteins, which eventually will trigger an anti-tumor immune response. It is of interest to note that BioNTech, the inventor of the hugely successful Comirnaty COVID-19 vaccine, originally started out as a developer of cancer immunotherapies.
On paper, monotherapy of mRNA vaccines can be sufficient to simulate cancer surface proteins and orchestrate a full-mount immune cell attack. However, early clinical data from monotherapies showed underwhelming efficacy and limited immune cell activation. This absence or insufficient activation and infiltration of immune cells to tumor tissue is what experts call a ‘cold’ tumor, in which inhibitory signals from tumor cells and the tumor microenvironment prevent a full-mount attack against tumor cells.
To elicit sufficient immune cell activation and antitumor activity, companies are pursuing combination therapies of mRNA vaccines with immune checkpoint inhibition. The past decade has taught us that combining cancer therapy with immune checkpoint inhibition can lead to potent synergies. The underlying strategy is to block inhibitory signaling pathways of many tumor tissues mutually and selectively upregulate to prevent an immune cell attack. Therefore, by combining mRNA vaccine therapy with checkpoint inhibitors, an active immune response against the tumor tissues can be mounted (Fig 3).
Figure 3: Mechanistic Insight of Complementary Synergies between mRNA Vaccines and Immune Checkpoint Inhibition for Oncology Settings.
Alternative approaches leveraging the mRNA technology in anti-cancer therapies focus on neoantigens. As these neoantigens are cancer- and patient-specific, the therapies should express higher immunogenicity and open the possibility to be used in a mono-therapeutic approach. However, in this article, we will focus on the advanced pipeline of mRNA therapies in combination with checkpoint inhibitors. Table 1 below summarizes the most advanced pipeline candidates.
Table 1: Selected mRNA Vaccine Pipeline by Company and Indication.
Also, it can be noted that the advanced oncology pipeline for mRNA vaccine candidates has a clear focus on aggressive solid tumors with high mutation burden such as melanoma, colorectal carcinoma, and non-small cell lung cancer. Thus far, companies have focused on indications using three main prioritization criteria:
High unmet need, characterized by advanced tumors with insufficient immune cell activation and infiltration
Established biological targets, with limited inter-patient variation of the tumor cell-specific protein expression patterns
High commercialization potential with incidence rates of more than 1MM new patients globally each year
Many trials have yet to report results; however, first preliminary data have shown promising tumor-specific T cell activation and pronounced antitumor immunity. Further readouts are expected in the second half of 2022 and are eagerly awaited by the industry, as results will provide further guidance for the nascent and emerging field.
COVID has brought mRNA technologies to the global center stage of attention. Beyond their natural application in immunology, mRNA vaccines have also caught attention in oncological applications. However, mRNA vaccines as monotherapy are less effective, specifically in tumors where the expression of immune response-triggering surface proteins is counteracted by the tumor microenvironment. Early clinical results of combination therapeutics of mRNA vaccines and checkpoint inhibitors overcome this specific challenge, and the concept is currently being tested in melanoma, NSCLC, and colorectal cancers. It remains to be seen if the concept of combination therapies with mRNA vaccines can be extended to other tumor applications or checkpoint inhibitors as combination.
 Sahin 2014 Nature Reviews Drug Discovery (https://www.nature.com/articles/nrd4278)
 Miao 2021 Molecular Cancer (https://doi.org/10.1186/s12943-021-01335-5)
 Jackson 2020 NPJ Vaccines (https://www.nature.com/articles/s41541-020-0159-8)
 Chalmers 2017 Genome Medicine (https://doi.org/10.1186/s13073-017-0424-2)
 Fierce Biotech (https://www.fiercebiotech.com/biotech/strand-snags-52m-to-develop-next-gen-mrna-meds-for-cancer)
 Beck 2021 Mol Cancer (https://pubmed.ncbi.nlm.nih.gov/33858437/ )
 Fierce Biotech (https://www.fiercebiotech.com/biotech/sanofi-inks-3-2b-translate-buyout-to-get-deeper-into-mrna-r-d)
 Fierce Biotech (https://www.fiercebiotech.com/biotech/sanofi-pays-160m-for-mrna-tech-to-reprogram-t-cells-vivo)
 BioNTech (https://investors.biontech.de/news-releases/news-release-details/biontech-announces-first-patient-dosed-phase-2-clinical-trial)
Holger Müller is a Vice President and leads Health Advances’ European office. He works primarily with biopharmaceutical clients supporting them to bring innovative technologies to the market.