Bedside formulation of a personalized multi-neoantigen vaccine against mammary carcinoma
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/440778v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@88f5d3org.highwire.dtl.DTLVardef@1c32c71org.highwire.dtl.DTLVardef@9abbedorg.highwire.dtl.DTLVardef@a7f41a_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO Individualized neoantigen vaccination against mammary carcinoma C_FIG BackgroundHarnessing the immune system to purposely recognize and destroy tumours represents a significant breakthrough in clinical oncology. Nonsynonymous mutations (neoantigenic peptides) were identified as powerful cancer targets. This knowledge can be exploited for further improvements of active immunotherapies, including cancer vaccines as T cells specific for neoantigens are not attenuated by immune tolerance mechanism and do not harm healthy tissues. The current study aimed at developing an optimized multi-target vaccine using short or long neoantigenic peptides utilizing virus-like particles (VLPs) as an efficient vaccine platform. MethodsHere we identified mutations of murine mammary carcinoma cells by integrating mass spectrometry-based immunopeptidomics and whole exome sequencing. Neoantigenic peptides were synthesized and covalently linked to virus-like nanoparticles using a Cu-free click-chemistry method for easy preparation of vaccines against mouse mammary carcinoma. ResultsAs compared to short peptides, vaccination with long peptides was superior in the generation of neoantigen-specific CD4+ and CD8+ T cells which readily produced IFN-{gamma} and TNF-. The resulting anti-tumour effect was associated with favourable immune re-polarization in the tumour microenvironment through reduction of myeloid-derived suppressor cells. Vaccination with long neoantigenic peptides also decreased post-surgical tumour recurrence and metastases, and prolonged mouse survival, despite the tumours low mutational burden. ConclusionIntegrating mass spectrometry-based immunopeptidomics and whole exome-sequencing is an efficient technique for identifying neoantigenic peptides. A multi-target VLP-based vaccine shows a promising anti-tumour results in an aggressive murine mammary carcinoma cell line. Future clinical application using this strategy is readily feasible and practical, as click-chemistry coupling of personalized synthetic peptides to the nanoparticles can be done at the bedside directly before injection.