Emerging prospects of mRNA cancer vaccines: mechanisms, formulations, and challenges in cancer immunotherapy

Abstract

Cancer continues to pose an alarming threat to global health, necessitating the need for the development of efficient therapeutic solutions despite massive advances in the treatment. mRNA cancer vaccines have emerged as a hopeful avenue, propelled by the victory of mRNA technology in COVID-19 vaccines. The article delves into the intricate mechanisms and formulations of cancer vaccines, highlighting the ongoing efforts to strengthen mRNA stability and ensure successful translation inside target cells. Moreover, it discusses the design and mechanism of action of mRNA, showcasing its potential as a useful benchmark for developing efficacious cancer vaccines. The significance of mRNA therapy and selecting appropriate tumor antigens for the personalized development of mRNA vaccines are emphasized, providing insights into the immune mechanism. Additionally, the review explores the integration of mRNA vaccines with other immunotherapies and the utilization of progressive delivery platforms, such as lipid nanoparticles, to improve immune responses and address challenges related to immune evasion and tumor heterogeneity. While underscoring the advantages of mRNA vaccines, the review also addresses the challenges associated with the susceptibility of RNA to degradation and the difficulty in identifying optimum tumor-specific antigens, along with the potential solutions. Furthermore, it provides a comprehensive overview of the ongoing research efforts aimed at addressing these hurdles and enhancing the effectiveness of mRNA-based cancer vaccines. Overall, this review is a focused and inclusive impression of the present state of mRNA cancer vaccines, outlining their possibilities, challenges, and future predictions in the fight against cancer, ultimately aiding in the development of more targeted therapies against cancer.

Keywords: cancer; immune response; immunotherapy; mRNA; vaccine.

Figure 1

An overview of modified mRNA transcript for mRNA vaccine.

Figure 2

Schematic representation of designing mechanism of mRNA vaccine and its mode of action inside the cells. Step 1: The marked antigen sequence is designed and then introduced into the plasmid DNA vector when the tumor genome has been accomplished. Step 2: Artificial mRNA designed by in vitro transcription using the linearized plasmid DNA template is purified. Step 3: The purified mRNA is combined with delivery intermediaries to produce the mRNA vaccine. Step 4: Endocytosis takes the mRNA vaccine up inside the cells. Step 5: Release of the marked mRNA into the cytoplasm. Step 6: The ribosome translates the mRNA into protein. Step 7: The proteasome complex breaks down the protein product into antigenic peptide epitopes. Step 8: In the endoplasmic reticulum, the antigenic epitopes are loaded onto MHC class I molecules. Step 9: MHC class I molecules deliver CD8+ T cells antigenic peptides. Interchangeably, the protein product is designed, captivated by the cell, and then uncovered to an endosomal degradation process in step 10. Step 11: MHC class II molecules present the antigenic fragments to T-helper cells on the cell surface. Step 12: T-helper cells prompt B cells to make antibodies that neutralize target-specific cancer antigens. MHC, main histocompatibility complex, BCR and TCR, T cell and B cell surface receptor. The figure illustrates the overview of modified mRNA for mRNA vaccine production. The structure of mRNA is presented, starting from the 5’ cap, followed by the 5’ untranslated region (UTR), the coding region with chemically modified bases, and the 3’ untranslated region (UTR) with a poly(A) tail. The modifications shown include methylation and isomerization of bases: N6-methyladenosine (m6A), 5-methyluridine (m5U), 2-thiouridine (s2U), pseudouridine (Ψ), N1-methylpseudouridine (m1Ψ), and 5-methylcytidine (m5C), among others. These modifications occur at adenosine, uridine, and cytidine bases, providing specific structural and functional benefits.

Figure 3

Key components involved in mRNA-LNP formulation. A typical LNP includes four key components, namely Ionizable cationic lipids, Phospholipids, PEGylated lipids, and Cholesterol. Ionizable cationic lipids generally employed for LNP formulation include DLin-DMA; DLin-KC2-DMA; DLin-MC3-DMA; cKK-E12; and C12-200. Phospholipids, such as 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), are frequently utilized in this regard. Additionally, PEGylated lipids used for LNP formulation include ALC-0159 and DMG-PEG 2000. Cholesterol is also incorporated in the LNP to maintain its structural integrity. Finally, the mRNA cargo loaded within LNP includes the mRNA sequence of critical genes encoding Tumor-Associated Antigens (TAAs).