Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia

Candice R. Gurbatri, Georgette A. Radford, Laura Vrbanac, Jongwon Im, Elaine M. Thomas, Courtney Coker, Samuel R. Taylor, YoungUk Jang, Ayelet Sivan, Kyu Rhee, Anas A. Saleh, Tiffany Chien, Fereshteh Zandkarimi, Ioana Lia, Tamsin R. M. Lannagan, Tongtong Wang, Josephine A. Wright, Hiroki Kobayashi, Jia Q. Ng, Matt Lawrence, Tarik Sammour, Michelle Thomas, Mark Lewis, Lito Papanicolas, Joanne Perry, Tracy Fitzsimmons, Patricia Kaazan, Amanda Lim, Alexandra M. Stavropoulos, Dion A. Gouskos, Julie Marker, Cheri Ostroff, Geraint Rogers, Nicholas Arpaia, Daniel L. Worthley, Susan L. Woods () and Tal Danino ()
Additional contact information
Candice R. Gurbatri: Columbia University
Georgette A. Radford: University of Adelaide
Laura Vrbanac: University of Adelaide
Jongwon Im: Columbia University
Elaine M. Thomas: University of Adelaide
Courtney Coker: Columbia University
Samuel R. Taylor: Weill Cornell-Rockefeller-Sloan Kettering Tri-Institutional MD-PhD program
YoungUk Jang: Columbia University
Ayelet Sivan: Columbia University
Kyu Rhee: Weill Cornell Medicine
Anas A. Saleh: Weill Cornell Medicine
Tiffany Chien: Columbia University
Fereshteh Zandkarimi: Columbia University
Ioana Lia: Columbia University
Tamsin R. M. Lannagan: University of Adelaide
Tongtong Wang: University of Adelaide
Josephine A. Wright: South Australian Health and Medical Research Institute (SAHMRI)
Hiroki Kobayashi: University of Adelaide
Jia Q. Ng: University of Adelaide
Matt Lawrence: Royal Adelaide Hospital
Tarik Sammour: University of Adelaide
Michelle Thomas: Royal Adelaide Hospital
Mark Lewis: Royal Adelaide Hospital
Lito Papanicolas: South Australian Health and Medical Research Institute (SAHMRI)
Joanne Perry: Royal Adelaide Hospital
Tracy Fitzsimmons: Royal Adelaide Hospital
Patricia Kaazan: University of Adelaide
Amanda Lim: University of Adelaide
Alexandra M. Stavropoulos: University of Adelaide
Dion A. Gouskos: University of Adelaide
Julie Marker: Cancer Voices SA
Cheri Ostroff: University of South Australia
Geraint Rogers: South Australian Health and Medical Research Institute (SAHMRI)
Nicholas Arpaia: Vagelos College of Physicians and Surgeons of Columbia University
Daniel L. Worthley: South Australian Health and Medical Research Institute (SAHMRI)
Susan L. Woods: University of Adelaide
Tal Danino: Columbia University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-44776-4

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