Editorial: mRNA Vaccines and Immunotherapy in Oncology: A New Era for Personalized Medicine.

Synthetic mRNA and the expression of therapeutic proteins have accelerated vaccine development to prevent infection and heralds a new era in targeted immunotherapy in oncology. Therapeutic mRNA vaccines rely on available tumor tissue for gene sequencing analysis to compare the patient's normal cellular DNA sequences and those of the tumor. Carrier-based mRNA vaccines for cancer immunotherapy are now in development that use delivery systems based on peptides, lipids, polymers, and cationic nano-emulsions. There have also been recent developments in dendritic cell-based mRNA vaccines. For patients with available tumor tissue samples, it is possible to develop mRNA vaccines that result in the expression of tumor antigens by antigen-presenting cells (APCs), resulting in innate and adaptive immune responses. Ongoing developments in mRNA immunotherapy include modifications in the route of administration and combined delivery of multiple mRNA vaccines with checkpoint inhibitors. This Editorial aims to present a brief overview of how mRNA immunotherapy may change the therapeutic landscape of personalized medicine for patients with solid malignant tumors.

The rationale for developing mRNA-based vaccines for cancer immunotherapy is not to prevent cancer but to destroy tumor cells in the patient [1,2]. Initial preclinical studies on mRNA vaccines were conducted in animal models and showed efficacy that was not supported in clinical studies [2,3]. In the past decade, there have been rapid developments in checkpoint inhibitors, vaccine adjuvants, vaccine delivery systems, and increased understanding of the tumor microenvironment, including the roles of antigen-presenting cells (APCs) [4]. Other challenges to mRNA vaccine development included the instability of mRNA and its low immunogenicity, which initially resulted in poor immune responses [4]. These initial challenges were overcome by mRNA sequence optimization, and current advantages of mRNA vaccines include their safety and efficacy and the ability for manufacturing on a mass scale [3,4],

Preclinical studies also showed that the use of isolated mRNA without a delivery vector did not result in an adequate antibody-mediated immune response, which explains why some mRNA vaccines are coupled with an immunologic adjuvant [5]. Also, carrier-based mRNA vaccines for cancer immunotherapy are now in development that use delivery systems based on peptides, lipids, polymers, and cationic nano-emulsions [5]. There have also been some recent developments in dendritic cell-based mRNA vaccines [5]. Vaccination with isolated mRNA, or vehicle-loaded mRNA, results in tumor antigen expression by APCs, which leads to activation of the innate and adaptive immune responses [13].

From 2020, the COVID-19 pandemic accelerated the development of synthetic mRNA vaccines for SARS-CoV-2 [68]. Moderna (Cambridge, MA, USA) and BioNTech (Mainz, Germany) developed the first approved mRNA vaccines for SARS-CoV-2, which are now being administered worldwide [8]. Both Moderna and BioNTech have established immuno-oncology mRNA vaccine pipelines, with ongoing clinical trials [9,10]. For example, the Moderna personalized cancer vaccine (PCV) mRNA-4157 was developed because mutations are rarely shared between patients [9,11]. The mRNA-4157 vaccine is a lipid-encapsulated mRNA that encodes 34 novel antigens that activate specific T-cells to target malignant cells [9,11]. The KEYNOTE-603 trial was conducted on the safety and efficacy of mRNA-4157 as a monotherapy in 16 patients and in combination with pembrolizumab (Merck, Darmstadt, Germany) in 63 patients with solid tumors, which included ten patients with head and neck squamous cell carcinoma (HNSCC) [12]. In the HNSCC group, the overall response rate (ORR) was 50%, three patients achieved partial remission (PR), two patients achieved complete remission (CR), and four patients had stable disease (SD) [12]. These findings represented a disease control rate of 90%, with a median progression-free survival (PFS) of 9.8 months [12]. The KEYNOTE-603 trial was associated with only low-grade and reversible treatment-related adverse events [12].

Accelerated development, manufacture, clinical trials, and approvals of mRNA vaccines have been propelled in the past year by the COVID-19 pandemic [8]. An important outcome from the current interest in mRNA vaccines has highlighted their potential role in personalized medicine and therapeutics in oncology [13]. In the future, there will be increased collaboration between academic institutions, large pharmaceutical companies, and small biotech companies to develop and trial new mRNA vaccines. Development of future tumor tissue-based laboratory diagnostics are likely to follow, with standardization, guidelines, and regulatory approval for the widespread use of these gene sequencing diagnostics in clinical laboratories as targeted mRNA vaccine therapy in oncology becomes increasingly available [13].

Conclusions

In oncology, mRNA vaccines for immunotherapy have undergone accelerated clinical development following regulatory approvals of mRNA vaccines to SARS-CoV-2. Because mRNA vaccines for personalized oncology immunotherapy rely on tumor tissue for gene sequencing, it is anticipated that laboratory molecular diagnostics will undergo rapid development and authorization for routine use to support a new era for personalized medicine.