Development of a mesothelin-based prophylactic vaccine against ovarian cancer

Abstract

Abstract Mesothelin is a tumor-associated antigen overexpressed in ovarian cancer and normally expressed by mesothelial linings. While mesothelin function remains to be fully elucidated, the lack of phenotype of mesothelin-knockout mice makes it plausible that mesothelin can safely serve as a vaccine target. We designed a new vaccination strategy based on mesothelin targeting with activation of type I IFN signaling via cyclic dinucleotides (CDN). Vaccines first combined human mesothelin protein with alum- vs. CDN-based adjuvants. C57Bl/6 mice received a priming immunization followed by 2 boosts; two weeks later, immunized mice were injected orthotopically with luciferase-transduced mouse ovarian cancer cells (Luc-ID8). More than 2/3 of the mesothelin/CDN-immunized mice were protected against invasive cancer and presented increased cytotoxic T cells (CTL) and plasmacytoid dendritic cells in spleens. Effector memory T cells were also increased and MDSC were profoundly decreased in peritoneal lavages after immunization with mesothelin +/− CDN compared with all the other groups. IFNγ ELISPOT assays performed with protected animal splenocytes stimulated with mesothelin peptides identified 2 immunogenic regions. We next tested a peptide-based subunit vaccine derived from mouse mesothelin sequence. Immunization and 2 boosts of 25-mer peptides with CDN were sufficient to mount an immune response against 2 overlapping mouse mesothelin peptides. Immunizations with peptide pools mapping in the immunogenic regions are currently assessed for protection against Luc-ID8 growth and progression. Peptide-based prophylactic vaccination against ovarian cancer may be possible in combination with adjuvants that trigger cellular immunity.