Abstract 717: Mouse model for the development of preventive and therapeutic vaccines against microsatellite-unstable cancers

Abstract

Abstract Microsatellite-unstable (MSI) cancers occurring in the context of Lynch syndrome elicit pronounced tumor-specific immune responses. These immune responses are specifically directed against frameshift peptide (FSP) neoantigens, which result from mismatch repair (MMR) deficiency-induced insertion/deletion mutations in coding microsatellites (cMS). We have recently completed a clinical phase I/IIa trial that successfully demonstrated safety and immunogenicity of an FSP neoantigen-based vaccine in MSI colorectal cancer patients (Clinical trial number: NCT01461148). To further develop a vaccine against MSI cancers in Lynch syndrome, we aimed to establish a preclinical mouse model. A systematic database search was performed to identify cMS sequences in the murine genome. Subsequently, intestinal cancers obtained from Lynch syndrome mice (Msh2flox/flox VpC+/+) were evaluated for mutations affecting these candidate microsatellites. Thirteen candidate cMS were detected that presented with a mutation frequency of 15% or higher. The cMS most frequently affected by frameshift mutations was located in the Nacad gene (75% of tested tumors). Epitope prediction using the netMHC4.0 algorithm was performed, and ten most promising FSP neoantigens were synthesized. Immunogenicity was evaluated after vaccination of C57BL/6 mice using IFN-gamma ELISpot. Four FSP neoantigens derived from cMS mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular immune responses. CD4-specific T cell responses were detected for Maz(-1), Nacad(-1), and Senp(-1), all of which also induced humoral immune responses. CD8-positive T cells were detected for Xirp(-1) and Nacad(-1). Preliminary epitope mapping indicated that there was no cross-reactivity with the respective wild type proteins. Based on mutation data, a vaccine with the four FSP neoantigens has a predicted coverage of up to 75% of intestinal tumors in the Msh2flox/flox VpC+/+ Lynch mouse model. In summary, we have identified 4 immunogenic FSP neoantigens derived from commonly mutated cMS in murine Lynch syndrome colorectal cancers. These results provide the basis for evaluating the concept of cancer-preventive FSP vaccines in a mouse model of Lynch syndrome. This model allows longitudinal monitoring of immune responses and tumor development using different vaccination schemes, adjuvants and combination with chemoprevention. Citation Format: Matthias Kloor, Mine Oezcan, Aysel Ahadova, Yan Yuan, Peer Bork, Shizuko Sei, Robert Shoemaker, Oezkan Gelincik, Steven Lipkin, Johannes Gebert, Magnus von Knebel Doeberitz. Mouse model for the development of preventive and therapeutic vaccines against microsatellite-unstable cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 717.