Abstract

Cancer vaccines, designed to activate the body’s own immune system to fight against tumors, are a current trend in cancer treatment and receiving increasing attention. Cancer vaccines mainly include oncolytic virus vaccine, cell vaccine, peptide vaccine and nucleic acid vaccine. Over the course of decades of research, oncolytic virus vaccine T-VEC, cellular vaccine sipuleucel-T, various peptide vaccines, and DNA vaccine against HPV positive cervical cancer have brought encouraging results for cancer therapy, but are losing momentum in development due to their respective shortcomings. In contrast, the advantages of mRNA vaccines such as high safety, ease of production, and unmatched efficacy are on full display. In addition, advances in technology such as pseudouridine modification have cracked down the bottleneck for developing mRNA vaccines including instability, innate immunogenicity, and low efficiency of in vivo delivery. Several cancer mRNA vaccines have achieved promising results in clinical trials, and their usage in conjunction with other immune checkpoint inhibitors (ICIs) has further boosted the efficiency of anti-tumor immune response. We expect a rapid development of mRNA vaccines for cancer immunotherapy in the near future. This review provides a brief overview of the current status of mRNA vaccines, highlights the action mechanism of cancer mRNA vaccines, their recent advances in clinical trials, and prospects for their clinical applications.

Introduction

Cancer is currently one of the most challenging problems adversely affecting human health. The unique immunosuppressive state of the tumor microenvironment (TME) attracts much attention in the field of cancer therapy. Cancer immunotherapy aims to boost the patient’s anti-tumor immune system, change the TME, promote cancer cell death and ultimately improve the cancer survival rate. Although ICIs have been proved to be effective in treating a variety of cancers, the overall response rate in patients is quite moderate. So, there is an urgent need to enhance the efficacy of current cancer immunotherapies.

Cancer vaccine is a major breakthrough in use of antigens to activate the human immune system against malignant tumors. Cancer vaccines fall into several broad categories, including oncolytic viruses (OVs), cellular vaccine, peptide vaccine, and nucleic acid vaccine.

OVs are natural or genetically engineered viruses that can infect and replicate in cancer cells, thereby directly killing infected cells and inducing systemic anti-tumor immunity [1,2]. Several OVs have entered into clinical trials such as adenovirus, poxviruses, herpes simplex virus type I (HSV-1), and coxsackievirus [3]. Talimogene laherparepvec (T-VEC), the first attenuated HSV-1 vaccine approved by the FDA, encodes granulocyte-macrophage colony-stimulating factor (GM-CSF) and promotes anti-tumor immune response and prolongs the median survival rate of patients with melanoma [2,[4], [5], [6]]. In addition, OVs have a synergistic effect on cancer therapy in combination with chemotherapy, radiotherapy or chimeric antigen receptor T cell (CAR-T) immunotherapy [1,7,8]. It also shows the potential of transforming immunosuppressive “cold” tumors into “hot” tumors [9]. However, OVs are live viruses prone to propagation, which may lead to uncontrollable dose changes and suffering from the host antiviral immune response [10].

Conclusion and perspectives

With the development of molecular biology, mRNA vaccines have brought unprecedented hopes for cancer immunotherapy. Historically, the use of mRNA vaccines has been limited by instability, innate immunogenicity and low efficiency of in vivo delivery. Improvements in mRNA structure (e.g., codon optimization, nucleotide modification, selfamplifying mRNA; etc.) and delivery vehicles (e.g., LNPs, polymers, peptides;etc.) have largely overcome these barriers. Compared to other cancer vaccines, mRNA vaccines stand out for several reasons: (1) An mRNA vaccine can encode multiple antigens simultaneously which bind to both MHC-I and MHC-II to promote humoral and cellular immune responses. (2) Compared to DNA vaccines, mRNA vaccines are nonintegratable, therefore free of mutagenic risk. (3) mRNA produced by IVT is free of pathogenic viral components and with no potential of infection. (4) Cancer mRNA vaccines offer the advantages with low costs, rapid production, and convenient renewal.

However, the mRNA field still faces challenges in terms of immunogenicity and effectiveness. Systemic inflammatory response may be the main concern for mRNA cancer vaccines, as mRNA inherently possesses immunostimulatory functions by activating the TLR7/8 pathway and inducing an IFN-I response. Currently, the innate immune response mediated by IFN-I can be largely reduced by removal of dsRNA contaminants, codon optimization and nucleotide modification. Another challenge is to determine the most feasible administration route for the vaccine. The administration route dictates the distribution of mRNA and influences the vaccine’s efficacy. Muscle injection is a common and viable administration route, currently, FDA-approved SARS-CoV-2 mRNA vaccines are delivered through muscle injection [114]. However, intravenous injection allows mRNA to reach many lymphoid organs, and this administration method has been proven to stimulate a robust CD8+ T cell anti-tumor immune response. Therefore, intravenous injection is the most commonly used direct administration route in mRNA cancer vaccine trials.