Intratumoural production of TNFα by bacteria mediates cancer therapy

Systemic administration of the highly potent anticancer therapeutic, tumour necrosis factor alpha (TNFα) induces high levels of toxicity and is responsible for serious side effects. Consequently, tumour targeting is required in order to confine this toxicity within the locality of the tumour. Bacter...

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Bibliographic Details
Published in:PloS one 2017-06, Vol.12 (6), p.e0180034-e0180034
Main Authors: Murphy, Carola, Rettedal, Elizabeth, Lehouritis, Panos, Devoy, Ciarán, Tangney, Mark
Format: Article
Language:English
Subjects:
Animal models
Animals
Antigens
Bacteria
Biocompatibility
Biology and Life Sciences
Bioluminescence
Cancer
Cancer therapies
Colon
Colorectal Neoplasms - microbiology
Colorectal Neoplasms - therapy
E coli
Enzyme-linked immunosorbent assay
Escherichia coli - growth & development
Escherichia coli - metabolism
Gene expression
Gene therapy
Immunofluorescence
In vivo methods and tests
Inflammation
Intravenous administration
Kidney cancer
Kidney Neoplasms - microbiology
Kidney Neoplasms - therapy
Kidneys
Male
Medical research
Medicine and Health Sciences
Mice
Mice, Inbred BALB C
Plasmids
Prostate
Prostate cancer
Prostatic Neoplasms - microbiology
Prostatic Neoplasms - therapy
Research and Analysis Methods
Side effects
Survival
TNF inhibitors
Toxicity
Tumor necrosis factor
Tumor Necrosis Factor-alpha - biosynthesis
Tumor necrosis factor-TNF
Tumors
Vectors (Biology)
Vehicles
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Summary:Systemic administration of the highly potent anticancer therapeutic, tumour necrosis factor alpha (TNFα) induces high levels of toxicity and is responsible for serious side effects. Consequently, tumour targeting is required in order to confine this toxicity within the locality of the tumour. Bacteria have a natural capacity to grow within tumours and deliver therapeutic molecules in a controlled fashion. The non-pathogenic E. coli strain MG1655 was investigated as a tumour targeting system in order to produce TNFα specifically within murine tumours. In vivo bioluminescence imaging studies and ex vivo immunofluorescence analysis demonstrated rapid targeting dynamics and prolonged survival, replication and spread of this bacterial platform within tumours. An engineered TNFα producing construct deployed in mouse models via either intra-tumoural (i.t.) or intravenous (i.v.) administration facilitated robust TNFα production, as evidenced by ELISA of tumour extracts. Tumour growth was impeded in three subcutaneous murine tumour models (CT26 colon, RENCA renal, and TRAMP prostate) as evidenced by tumour volume and survival analyses. A pattern of pro-inflammatory cytokine induction was observed in tumours of treated mice vs. Mice remained healthy throughout experiments. This study indicates the therapeutic efficacy and safety of TNFα expressing bacteria in vivo, highlighting the potential of non-pathogenic bacteria as a platform for restricting the activity of highly potent cancer agents to tumours.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0180034