Probiotic neoantigen delivery vectors for precision cancer immunotherapy

Abstract

Microbial systems have been synthetically engineered to deploy therapeutic payloads in vivo1,2. With emerging evidence that bacteria naturally home in on tumours3,4 and modulate antitumour immunity5,6, one promising application is the development of bacterial vectors as precision cancer vaccines2,7. Here we engineered probiotic Escherichia coli Nissle 1917 as an antitumour vaccination platform optimized for enhanced production and cytosolic delivery of neoepitope-containing peptide arrays, with increased susceptibility to blood clearance and phagocytosis. These features enhance both safety and immunogenicity, achieving a system that drives potent and specific T cell-mediated anticancer immunity that effectively controls or eliminates tumour growth and extends survival in advanced murine primary and metastatic solid tumours. We demonstrate that the elicited antitumour immune response involves recruitment and activation of dendritic cells, extensive priming and activation of neoantigen-specific CD4+ and CD8+ T cells, broader activation of both T and natural killer cells, and a reduction of tumour-infiltrating immunosuppressive myeloid and regulatory T and B cell populations. Taken together, this work leverages the advantages of living medicines to deliver arrays of tumour-specific neoantigen-derived epitopes within the optimal context to induce specific, effective and durable systemic antitumour immunity. Probiotic Escherichia coli Nissle 1917 is engineered as an antitumour vaccination platform optimized for enhanced production and cytosolic delivery of neoepitope-containing peptide arrays to safely induce specific, effective and durable systemic antitumour immunity.