Intratumoural production of TNF alpha by bacteria mediates cancer therapy

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dc.contributor.authorMurphy, Carola T.
dc.contributor.authorRettedal, Elizabeth
dc.contributor.authorLehouritis, Panos
dc.contributor.authorDevoy, Ciaran
dc.contributor.authorTangney, Mark
dc.contributor.funderBreakthrough Breast Cancer
dc.contributor.funderSeventh Framework Programme
dc.contributor.funderIrish Cancer Society
dc.date.accessioned2017-09-26T11:39:20Z
dc.date.available2017-09-26T11:39:20Z
dc.date.issued2017
dc.description.abstractSystemic administration of the highly potent anticancer therapeutic, tumour necrosis factor alpha (TNF alpha) 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. co/istrain MG1655 was investigated as a tumour targeting system in order to produce TNF alpha 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 TNF alpha producing construct deployed in mouse models via either intra-tumoural (i.t.) or intravenous (i.v.) administration facilitated robust TNF alpha 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. controls. Mice remained healthy throughout experiments. This study indicates the therapeutic efficacy and safety of TNF alpha 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.en
dc.description.sponsorshipIrish Cancer Society (PCI12TAN)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleide0180034
dc.identifier.citationMurphy, C., Rettedal, E., Lehouritis, P., Devoy, C. and Tangney, M. (2017) 'Intratumoural production of TNFα by bacteria mediates cancer therapy', PLoS ONE, 12(6), e0180034 (13pp). doi: 10.1371/journal.pone.0180034en
dc.identifier.doi10.1371/journal.pone.0180034
dc.identifier.issn1932-6203
dc.identifier.issued6
dc.identifier.journaltitlePLoS ONEen
dc.identifier.urihttps://hdl.handle.net/10468/4791
dc.identifier.volume12
dc.language.isoenen
dc.publisherPublic Library of Scienceen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP3::PEOPLE/612219/EU/Vaccines and Imaging Partnership/VIP
dc.relation.urihttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180034
dc.rights© 2017, Murphy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectNecrosis factor alphaen
dc.subjectGene therapyen
dc.subjectIonizing radiationen
dc.subjectDNA deliveryen
dc.subjectTumor growthen
dc.subjectSalmonellaen
dc.subjectTranscriptionen
dc.subjectMelanomaen
dc.subjectVectoren
dc.subjectSystemen
dc.titleIntratumoural production of TNF alpha by bacteria mediates cancer therapyen
dc.typeArticle (peer-reviewed)en
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