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bioRxiv · 10.1101/2021.04.24.440778

Bedside formulation of a personalized multi-neoantigen vaccine against mammary carcinoma

Mohsen, M. O.·Speiser, D. E.·Michaux, J.·Pak, H.·Stevenson, B. J.·Vogel, M.·Inchakalody, V. P.·de Brot, S.·Coukos, G.·Dermime, S.·Bassani-Sternberg, M.·Bachmann, M. F.
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Abstract

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.

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Mohsen, M. O., Speiser, D. E., Michaux, J., Pak, H., Stevenson, B. J., Vogel, M., Inchakalody, V. P., de Brot, S., Coukos, G., Dermime, S., Bassani-Sternberg, M., Bachmann, M. F.. 2021-04-26. Bedside formulation of a personalized multi-neoantigen vaccine against mammary carcinoma. https://doi.org/10.1101/2021.04.24.440778

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