Modi-2 a vaccine stimulating CD4 responses to homocitrullinated self epitopes as therapy for solid cancers

Abstract

Abstract Stresses within the tumour microenvironment can mediate post-translational modifications (PTM) of self-proteins. Homocitrullination is the conversion of lysine residues to homocitrulline which can generate neoepitopes and bypass self-tolerance. In this study a vaccine targeting homocitrullinated peptide antigens was assessed for its ability to stimulate anti-tumour immunity. Peptides that bind HLA are often hydrophobic which can lead to complications with large scale manufacture and solubility that must be considered in the design of vaccines. Here we demonstrate the use of a self-assembling nanoparticle technology (SNAPvaxTM) to co-deliver four homocitrullinated peptides and adjuvant in nanoparticles of a precise size and composition as a vaccine (“Modi-2”) that is optimized for manufacturing ease and T cell induction. The vaccine stimulated strong Th1 cell responses and anti-tumour immunity in mouse tumour models with 40% overall survival against B16 melanoma (p=0.0113), 100% survival against CT26 colorectal cancer (p<0.0001) and 70% survival against 4T1 breast cancer (p=0.0090). We demonstrate that human lung, colorectal, breast and prostate tumours express the antigens that are targets of the Modi-2 vaccine. We therefore propose the Modi-2 vaccine utilizing homocitrullinated peptides and SNAPvax has potential for translation into clinic in several cancer indications.