mRNA Therapeutics in Cancer Immunotherapy

Cancer is a group of life-threatening diseases involving abnormal cell growth with the potential to spread to other parts of the body. The treatment of cancer is full of challenges. Despite the improvements of conventional strategies, such as surgery, chemotherapy, and radiotherapy, they still do not prevent disease recurrence in many patients. The deeper knowledge of the tumor and its environment, especially the understanding of various immune cells (such as CD8+ T cells and natural killer cells) that have the capability to infiltrate tumors and help to kill tumor cells, has promoted the development of novel cancer therapy strategies. mRNA therapeutics as a novel cancer therapy strategy has received growing interest. At present, the applications of synthetic mRNAs in the immuno-oncology field are at high speed and have reached major milestones. Creative Biogene is a forward-looking research institute as well as a leading custom service provider in mRNA-based drug research and development (R&D). Our team is experienced in the customized synthesis of mRNA, mRNA optimization, and mRNA delivery system development. We are committed to offering high-quality customized service and the best outcome to accelerate the research progress for our global customers.

The applications of mRNA therapeutics for cancer immunotherapy

Synthetic mRNA has the capability to encode for almost any protein with an excellent safety profile as well as a flexible production process. The therapeutic potential of mRNA can be further enhanced through the modifications of mRNA molecules and the formulation of mRNA delivery systems. In this regard, synthetic mRNAs encoding tumor antigens have been extensively investigated for the development of potent cancer vaccines.

For the development of potent cancer vaccines, the selection of an appropriate antigen is an important and critical step. mRNA vaccines have a unique advantage that can be designed to target a wide variety of antigens, including tumor-associated antigens (TAAs), cancer testis antigens (CTAs) and tumor-specific antigens (TSAs) or neoantigen. TAAs are proteins that are significantly over-expressed in cancer compared to normal cells and can induce an anticancer response by triggering T cell recognition. CTAs belong to TAAs and can serve as ideal targets for cancer immunotherapy due to their robust immunogenicity and cancer-restricted expression. In general, neoantigens are mutated proteins presented on tumor cells due to mutation of DNA in cancer cells. Based on the whole exome and/or next-generation RNA sequencing, potential neoantigen targets can be identified after the analysis of the mutanome in an individual tumor, providing the basis for the development of personalized neoepitope cancer vaccines.

In addition to tumor antigen mRNA-based immunotherapy approaches, other means have also been studied, such as mRNA for delivery of mAbs, mRNA for induction of cancerous cell death, and mRNA for generation of tumor-specific T cells. These approaches have been demonstrated to be successful in preclinical studies, which further encouraged their evaluation in a clinical trial. The applications of mRNA therapeutics for cancer immunotherapy include,

• mRNA for tumor antigen vaccination.
• Delivery of cancer-specific and immune checkpoint blocking mAbs.
• Modulation of the tumor microenvironment.

-Modulation of suppressive cell types.

-Modulation of the cytokine milieu.

-Induction of cancerous cell death.

-Modulation of tumor-associated dendritic cells (DCs).

-Generation of tumor-specific T cells.

The in vivo application of mRNA to modulate the tumor microenvironment. (Van Hoecke, L.,et al, 2021)

Clinical overview of mRNA vaccines for cancer immunotherapy

Nowadays, there are numerous clinical trials using mRNA-based immunotherapy to treat various types of cancer. Despite the fact that they are in the early research stages, encouraging antitumor outcomes are expected. There are two main mRNA-based immunotherapy strategies,in vivo and ex vivo approaches. The first strategy is to directly deliver mRNA, involving naked mRNA or mRNA complexed with nanosystems, by different administration routes (local injection, such as intramuscular, subcutaneous, and intradermal injection, are major routes for mRNA vaccines in clinical studies). The latter strategy is based on the administration of mRNA-modified DCs or chimeric antigen receptor (CAR) T cells. mRNA vaccines have been utilized in the treatment of aggressive and less accessible solid tumors, including colorectal carcinoma (CRC), melanoma, non-small cell lung cancers (NSCLC), prostate cancer (PCa), etc. mRNA vaccine has also been investigated in treating glioblastoma for early proof of concept studies. The vaccines are further combined with checkpoint modulators or other treatment means to achieve better clinical antitumor potency.

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