Probiotic neoantigen delivery vectors for precision cancer immunotherapy

Microbial systems have been synthetically engineered to deploy therapeutic payloads in vivo 1 , 2 . With emerging evidence that bacteria naturally home in on tumours 3 , 4 and modulate antitumour immunity 5 , 6 , one promising application is the development of bacterial vectors as precision cancer v...

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Bibliographic Details
Published in:	Nature (London) Vol. 635; no. 8038; pp. 453 - 461
Main Authors:	Redenti, Andrew, Im, Jongwon, Redenti, Benjamin, Li, Fangda, Rouanne, Mathieu, Sheng, Zeren, Sun, William, Gurbatri, Candice R., Huang, Shunyu, Komaranchath, Meghna, Jang, YoungUk, Hahn, Jaeseung, Ballister, Edward R., Vincent, Rosa L., Vardoshivilli, Ana, Danino, Tal, Arpaia, Nicholas
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 14-11-2024 Nature Publishing Group
Subjects:	13/1 13/106 13/21 13/31 14/1 14/35 38/23 38/91 59/5 631/61/338/552 631/67/1059/2325 64/60 82/29 82/80 Adaptive immunity Antigens Antitumor activity Arrays Bacteria Biofilms Bone marrow Cancer Cancer immunotherapy CD4 antigen CD8 antigen Cell activation Cell survival Cell-mediated immunity Coliforms Dendritic cells E coli Epitopes Humanities and Social Sciences Immune clearance Immune response Immune response (cell-mediated) Immune system Immunity (Disease) Immunogenicity Immunotherapy Lymphocytes Lymphocytes T Metastases Microorganisms multidisciplinary Mutation Natural killer cells Neoantigens Payloads Peptides Phagocytosis Plasmids Probiotics Science Science (multidisciplinary) Solid tumors Tumors Vaccination Vaccines
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Summary:	Microbial systems have been synthetically engineered to deploy therapeutic payloads in vivo 1 , 2 . With emerging evidence that bacteria naturally home in on tumours 3 , 4 and modulate antitumour immunity 5 , 6 , one promising application is the development of bacterial vectors as precision cancer vaccines 2 , 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-024-08033-4