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, Young Uk 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 LawrenceTarik 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, Tal Danino

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number646
JournalNature Communications
Volume15
Issue number1
DOIs
Publication statusPublished or Issued - Dec 2024

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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