Abstract 2361: Novel animal models for prediction of cancer vaccine response

Abstract

Abstract Predicting cancer vaccine response is a challenge that must be addressed in immune competent animals that recapitulate human disease and human response to therapy. Furthermore, genetically heterogeneous humans respond differently to vaccination due, in part, to their varying MHC haplotypes and polymorphisms including those found in costimulatory or checkpoint genes. We previously showed that human HER2 transgenic (Tg) mice of different genetic backgrounds have distinct response to HER2 vaccines in the order of BALB > (BALBxB6)F1 > (B6xDR3)F1 > B6 (Radkevich-Brown 2010). We anticipate even greater variance among human populations, and seek genetically diverse animal models to project human cancer vaccine response. Domestic felines develop mammary tumors with similar pathology and etiology as human cancer, and expression of EGFR, HER2 and HER3 genes that are highly homologous to their human counterparts. Intramuscular electrovaccination of healthy outbred domestic shorthair cats with heterologous (xenogeneic) or single point-mutated self HER2 DNA induces HER2-specific T cells in ∼30% of vaccinated cats (Gibson 2015). Humoral immune responses were induced by both vaccine constructs, with point-mutated feline HER2 vaccine producing antibodies to unique epitopes on feline mammary carcinoma (FMC). The latter inhibits FMC growth in vitro and delays tumor growth in SCID mice. Vaccination with wild type feline HER2 DNA fails to induce specific immunity and even hinders feline HER2 immune activation by other vaccines. Studies in domestic cats provide novel insight on the range and nature of vaccine response in healthy cats which can also be tested in feline cancer patients. Strategic modification of minimal residues may be most effective in inducing reactivity to cancer associated self antigens. To address genetic regulation of vaccine response, diversity outbred (DO) mice offer a pragmatic option. These mice were generated by cross-breeding 8 inbred mouse strains to ensure broad genetic diversity among the mice (Svenson 2012). The human HER2 gene is introduced by breeding DO mice with our human HER2 transgenic (Tg) mice. F1 mice represent a genetically heterogeneous population that expresses human HER2 as a self antigen. Specific genes impacting vaccine response will be identified by genome-wide quantitative trait locus (QTL) scan to associate haplotype or single nucleotide variants with vaccine response. Findings in these mice may lead to the identification of critical genes that regulate cancer vaccine response. Candidate vaccines identified in DO mice can be further validated in cats and expanded to human trials. With these novel animal models, cancer vaccines can be designed and tested with greater precision, and patients with reactive genotypes may be identified before vaccination. (Supported by CA76340) Citation Format: Heather Gibson, Richard F. Jones, Joyce D. Reyes, Wei-Zen Wei. Novel animal models for prediction of cancer vaccine response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2361.