TY - JOUR
T1 - Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia
AU - Gurbatri, Candice R.
AU - Radford, Georgette A.
AU - Vrbanac, Laura
AU - Im, Jongwon
AU - Thomas, Elaine M.
AU - Coker, Courtney
AU - Taylor, Samuel R.
AU - Jang, Young Uk
AU - Sivan, Ayelet
AU - Rhee, Kyu
AU - Saleh, Anas A.
AU - Chien, Tiffany
AU - Zandkarimi, Fereshteh
AU - Lia, Ioana
AU - Lannagan, Tamsin R.M.
AU - Wang, Tongtong
AU - Wright, Josephine A.
AU - Kobayashi, Hiroki
AU - Ng, Jia Q.
AU - Lawrence, Matt
AU - Sammour, Tarik
AU - Thomas, Michelle
AU - Lewis, Mark
AU - Papanicolas, Lito
AU - Perry, Joanne
AU - Fitzsimmons, Tracy
AU - Kaazan, Patricia
AU - Lim, Amanda
AU - Stavropoulos, Alexandra M.
AU - Gouskos, Dion A.
AU - Marker, Julie
AU - Ostroff, Cheri
AU - Rogers, Geraint
AU - Arpaia, Nicholas
AU - Worthley, Daniel L.
AU - Woods, Susan L.
AU - Danino, Tal
N1 - Funding Information:
This work was supported in part by the National Institute of Health U01CA247573 (T.D.), National Institute of Health R01CA24916 (T.D.), the National Science Foundation Graduate Research Fellowship (1644869 to C.R.G.), Pershing Square Foundation (PSF) PSSCRA CU20-0730 (T.D.), Cancer Research Institute (CRI) CRI 3446 (T.D.) National Health and Medical Research Council (APP1184925 to S.L.W.), Cancer Council SA Beat Cancer Project on behalf of its donors and the State Government of South Australia through the Department of Health (MCF0418 to S.L.W.), the Gastroenterological Society of Australia Bushell Post-doctoral Research Fellowship (S.L.W.), the Faculty of Health Science at the University of Adelaide (S.L.W.), the South Australian Health and Medical Research Institute (S.L.W.).
Publisher Copyright:
© 2024, The Author(s).
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85182712180&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-44776-4
DO - 10.1038/s41467-024-44776-4
M3 - Article
AN - SCOPUS:85182712180
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 646
ER -