Identification, design, and in vivo proof of concept of a shared APC neoantigen delivered via a self-amplifying RNA containing virus-like nanoparticle for cancer vaccination.
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Colorectal Cancer (CRC) accounts for the second highest number of cancer-related mortalities rate worldwide, and its incidence and mortality is expected to continue to increase in the coming years. Over 80% of CRC cases are caused by mutation in the Adenomatous Polyposis Coli (APC) gene, a tumor suppressor gene involved in the Wnt signaling pathway that prevents uncontrolled cell growth. Familial Adenomatous Polyposis (FAP) is a rare, inherited, pediatric disorder characterized by the development of countless adenomatous (benign) polyps in the colon and/or rectum, and over the patient's lifetime there is an almost 100% likelihood that the disorder will progress into CRC. In this study, we utilized bioinformatics to identify shared neoantigen epitopes present at the mutational cluster region (MCR) of the APC gene of multiple CRC patients, where FAP-associated mutation is typically observed. We then developed and optimized a chimeric virus-like particle (VLP) to encapsulate an saRNA replicon encoding a neoantigen construct featuring the identified mutated APC sequences inserted into a WT APC backbone. T-cell specific activation and restimulation against neoantigen peptide fragments were observed in vitro, indicating the capacity for a T-cell mediated response in vivo. Serum samples from intramuscularly-dosed BALB/c mice exhibited significant neoantigen-specific IgG titers compared against vehicle control and WT APC control mice, confirming VLP-expression of neoantigens and indicating neoantigen-specific in vivo immune activity. The significant response observed against the nanoparticle-expressed APC neoantigen serves as proof-of-concept for a saRNA-expressed cancer vaccine against APC-associated CRC.