Abstract
Microsatellite-unstable (MSI) cancers occurring in the context of Lynch syndrome elicit pronounced tumor-specific immune responses 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). The vaccine was safe and induced robust cellular and humoral immune responses in all vaccinated patients. To further develop a cancer preventive 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 tumors 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. 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, Nacad, and Senp6 and CD8-positive T cells were detected for Xirp1 and Nacad. Vaccination with peptides encoding these four intestinal cancer FSP neoantigens promoted anti-neoantigen immunity, reduced intestinal tumorigenicity and prolonged overall survival (P<0.01). Additionally, NSAIDs, which have chemopreventive efficacy for Lynch syndrome, increase T cell immunity against neoantigens. Mechanistic tumor mutation burden and adaptive immune response studies will be shown. In summary, these data support the further development of vaccination strategies for preventing cancers associated with Lynch syndrome.
Citation Format: Ozkan Gelincik, Hamza Ibrahim, Mine Ozkan, Aysel Ahadova, Shizuko Sei, Robert Shoemaker, Mattias Kloor, Magnus Von Knebel Doeberitz, Steven M. Lipkin. Frameshift neoantigen vaccination prevent Lynch syndrome mouse model intestinal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2732.
RSS Feeds