Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia.
Candice R GurbatriGeorgette A RadfordLaura VrbanacJongwon ImElaine M ThomasCourtney CokerSamuel R TaylorYoungUk JangAyelet SivanKyu Y RheeAnas A SalehTiffany ChienFereshteh ZandkarimiIoana LiaTamsin R M LannaganTongtong WangJosephine A WrightHiroki KobayashiJia Q NgMatt LawrenceTarik SammourMichelle ThomasMark LewisLito PapanicolasJoanne PerryTracy FitzsimmonsPatricia KaazanAmanda Huoy Wen LimAlexandra M StavropoulosDion A GouskosJulie MarkerCheri OstroffGeraint RogersNicholas ArpaiaDaniel L WorthleySusan L WoodsTal DaninoPublished in: Nature communications (2024)
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.
Keyphrases
- clinical trial
- end stage renal disease
- small molecule
- chronic kidney disease
- newly diagnosed
- ejection fraction
- double blind
- escherichia coli
- randomized controlled trial
- study protocol
- phase iii
- phase ii
- skeletal muscle
- adipose tissue
- high grade
- high throughput
- placebo controlled
- combination therapy
- patient reported
- smoking cessation