MRNA-based vaccines were first brought to the immunotherapy field for their attractive ability to safely vaccinate against proteins harboring oncogenic driver mutations. Two years later, vaccination with a naked mRNA encoding cancer embryonic antigen (CEA) induced CEA-specific antibodies in mice, underscoring the anticancer potential of mRNA therapeutics ( 15– 17). In 1993, a liposome-mRNA construct expressing influenza hemagglutinin was reported to induce cytotoxic CD8 + T cell responses capable of detecting and lysing virus-infected cells in a murine model of influenza infection, demonstrating the immunogenic potential of RNA vectors ( 14). demonstrated the first successful RNA-mediated expression of a reporter transgene in vivo ( 13). History of mRNA-based vaccine strategiesĪs a novel expression platform, Malone and coworkers first documented the in vitro expression of a luciferase transgene from an mRNA vector ( 12). Understanding the advancements that yielded successful mRNA vaccines for COVID-19 should accelerate progress in overcoming the remaining challenges for their application to cancer vaccination. A large part of the more recently conducted foundational research that led to this success has rested on transformative biomedical engineering and novel delivery methods aimed to optimize the therapeutic potential of this vaccine platform. The SARS-CoV-2 pandemic led to the successful clinical development and application of several mRNA vaccines, underscoring the remarkable versatility, favorable immunogenicity, and overall safety of the mRNA platform on a global scale. But progress in mRNA vaccine clinical development has been slow because of challenges relating to stability, cost of personalized production of patient-specific vaccines, and delivery. The mRNA platform is also versatile and has successfully been used in systemic, subcutaneous, intramuscular, and in situ vaccine strategies and to genetically modify dendritic cell–based vaccines and create chimeric antigen receptor (CAR) T cell therapies. While many studies have used DNA or peptide platforms for cancer vaccine delivery, mRNA-based therapeutics have demonstrated equal or greater activity in preclinical studies and early-stage clinical trials. Preclinical and early-phase clinical trials testing neoantigen vaccines in immunologically insensitive cancers, such as pancreatic ductal adenocarcinoma and glioblastoma, have also shown promise in inducing neoantigen-specific antitumor immunity ( 8– 11). These studies have shown promise in activating robust and durable neoantigen-specific T cells, as well as early clinical responses, particularly in tumors such as melanoma that are more likely to respond to immune checkpoint blockade ( 3– 7). With the advent of bioinformatics tools, studies now focus on vaccines targeting neoantigens personalized to individual patients. Initial cancer vaccination strategies targeted antigens linked to oncogenesis and cancer progression that are shared by many cancers - either overexpressed cancer-initiating gene products (driver antigens) such as HER-2 or reactivated gene products such as MAGE ( 1, 2). For decades cancer vaccines have been utilized to induce antitumor immune responses against cancer antigens, sometimes in association with clinical responses.
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