Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia
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Date
2024
Authors
Gurbatri, C.R.
Radford, G.A.
Vrbanac, L.
Im, J.
Thomas, E.M.
Coker, C.
Taylor, S.R.
Jang, Y.
Sivan, A.
Rhee, K.
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Journal article
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Nature Communications, 2024; 15(646):646-1-646-13
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Candice R. Gurbatri ... Daniel L. Worthley ... Susan L. Woods ... Amanda Lim ... Georgette A. Radford ... Tracy Fitzsimmons ... Tarik Sammour ... Patricia Kaazan ... Michelle Thomas ... Laura Vrbanac ... Elaine M. Thomas ... Jia Q. Ng ... et al.
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Abstract
Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition and orthotopic models of CRC. We next undertake an interventional, double-blind, dual-centre, prospective clinical trial, in which CRC patients take either placebo or EcN for two weeks prior to resection of neoplastic and adjacent normal colorectal tissue (ACTRN12619000210178). We detect enrichment of EcN in tumor samples over normal tissue from probiotic-treated patients (primary outcome of the trial). Next, we develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate. Oral delivery of this strain results in increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. To assess therapeutic potential, we engineer EcN to locally release a cytokine, GM-CSF, and blocking nanobodies against PD-L1 and CTLA-4 at the neoplastic site, and demonstrate that oral delivery of this strain reduces adenoma burden by ~50%. Together, these results support the use of EcN as an orally-deliverable platform to detect disease and treat CRC through the production of screening and therapeutic molecules.
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Data source: Supplementary information, https://doi.org/10.1038/s41467-024-44776-4
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© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.