mRNA-Based Therapy for Colorectal Cancer

Colorectal cancer (CRC) originates from the cells of the colon or rectum and is currently the third most common cancer type in the world. CRC has a complex etiology in respect to environmental, genetic factors, and so on. Currently, the standard treatments for CRC include surgery, radiotherapy, and chemotherapy (alone or in combination). Although steady advances in treatment options have been made to improve overall survival in patients with CRC, the majority of these patients cannot be cured. Thus, there is an urgent need to investigate novel therapeutic strategies to fight against CRC. In this regard, immunotherapy as a set of novel approaches aims to remodel the immune system that battles with metastatic cancer cells, such as targeted treatments (immune checkpoint inhibitors), vaccination strategies (protein/peptide-based, DNA, and mRNA vaccine), cellular transplantation therapies (adoptive cell transfer, ACT). Here, we focus on the mRNA-based vaccine, an attractive field applied to treat colorectal cancer.

Key tumor antigens in CRC vaccine development

For the development of effective immunotherapy treatment strategies as well as specific cancer vaccines, one of the main steps is the identification of an appropriate antigen. There are two general classes of targets: tumor-associated antigens (TAAs) and tumor-specific antigens (TSA) 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. In CRC treatment, the most targeted TAAs are Mucin 1 (MUC-1), Wilms tumor 1 protein (WT1), Melanoma-Associated Antigen (MAGE), Carcinoembryogenic antigen (CEA), Epidermal growth factor receptor (EGFR), Epidermal growth factor receptor (EGFR), Survivin, and so on.

In addition, neoantigens are mutated proteins presented on tumor cells due to mutation of DNA in cancer cells. Neoantigens can be a nucleotide sequence or a polypeptide sequence. And they distinguish from the wild-type along with at least one change and one mutation. At present, according to CRC patients’ a unique set of sequences with originating of frame shift mutations, personalized cancer immunotherapy based on neoantigen is eagerly underway. Several neoantigens for making peptide-based vaccines are in clinical trials for CRC, including transforming growth factor beta receptor 2 (TGFβRII), mutant KRAS, CDX2, AIM2, TAF1B, and HT001. And other neoantigens for making vaccines are APC, KMT2D, ARID1A, SOX9, RNF43, TCF7L2, TP53, and so on.

Fig1. Comparison of tumor-associated antigens and tumor-specific antigens properties. (Wagner, S., et al, 2018)

mRNA-based therapy for CRC

In vitro synthesized mRNA-based vaccine has been investigated extensively as a therapeutic and prophylactic platform that encodes the cancer-specific antigen(s). Recently, there have been several early-stage clinical trials suggesting the potential of mRNA-based vaccines for CRC.

Fig 2. The comparative safety, immunogenicity and efficacy profile of protein/peptide, DNA, and mRNA vaccines (based on evidence from recent CRC clinical trials). (Shahnazari, M., et al, 2020)

mRNA 4650 (NCI 4650)

mRNA 4650 is a mRNA-based cancer vaccine encoding cancer’s specific neoantigens and is underway for the treatment of various cancers, including CRC. In phase I/II trial, the results demonstrated that intramuscularly administered mRNA 4650 was safe and elicited CD8, CD4 T cells responses against CRC neoantigens. mRNA 4650 combined with checkpoint inhibitors or adoptive T cell therapy can introduce more effective immunotherapy strategies in common epithelial cancer patients.

mRNA 4157

mRNA 4157, another mRNA-based cancer vaccine, is designed to encode up to 34 unique neoantigens for provoking the CD8 and CD4 T cell responses. It is reported that mRNA-4157 as monotherapy and in combination with PD-1 inhibitor therapy (pembrolizumab) had a good safety profile, and induced significant levels of neoantigen-specific T cells, resulting in partial and complete responses in patients with MSI-high CRC.

mRNA 5671 (V 941)

mRNA 5671 is a therapeutic cancer vaccine that encodes the four most commonly occurring KRAS mutations (G12D, G12V, G13D and G12C) to trigger T cell immune system. mRNA 5671 fights against KRAS positive cancers, therefore, the same applies to CRC. In preclinical studies, the results of mRNA 5671 as a monotherapy and in combination with pembrolizumab also greatly promoted CD8 T cell anti-cancer response. Regarding therapeutic efficacy, safety, immunogenicity, and tolerability of mRNA 5671, phase I study is underway.

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 devoted to offering high-quality service and achieving the best outcome for our customers from all over the world. If you are interested in this area, please feel free to contact us. We look forward to providing services for your next project.

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