title: Advancing Clostridia to Clinical Trial: Past Lessons and Recent Progress.
abstract: Most solid cancers contain regions of necrotic tissue. The extent of necrosis is associated with poor survival, most likely because it reflects aggressive tumour outgrowth and inflammation. Intravenously injected spores of anaerobic bacteria from the genus Clostridium infiltrate and selectively germinate in these necrotic regions, providing cancer-specific colonisation. The specificity of this system was first demonstrated over 60 years ago and evidence of colonisation has been confirmed in multiple tumour models. The use of "armed" clostridia, such as in Clostridium Directed Enzyme Prodrug Therapy (CDEPT), may help to overcome some of the described deficiencies of using wild-type clostridia for treatment of cancer, such as tumour regrowth from a well-vascularised outer rim of viable cells. Successful preclinical evaluation of a transferable gene that metabolises both clinical stage positron emission tomography (PET) imaging agents (for whole body vector visualisation) as well as chemotherapy prodrugs (for conditional enhancement of efficacy) would be a valuable early step towards the prospect of "armed" clostridia entering clinical evaluation. The ability to target the immunosuppressive hypoxic tumour microenvironment using CDEPT may offer potential for synergy with recently developed immunotherapy strategies. Ultimately, clostridia may be most efficacious when combined with conventional therapies, such as radiotherapy, that sterilise viable aerobic tumour cells.
authors.affiliation: Translational Therapeutics Team, Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland 1023, New Zealand. a.mowday@auckland.ac.nz.|Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, University of Auckland, Auckland 1023, New Zealand. a.mowday@auckland.ac.nz.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Mowday
authors.affiliation: Translational Therapeutics Team, Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland 1023, New Zealand. c.guise@auckland.ac.nz.|Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, University of Auckland, Auckland 1023, New Zealand. c.guise@auckland.ac.nz.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Guise
authors.affiliation: Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, University of Auckland, Auckland 1023, New Zealand. david.ackerley@vuw.ac.nz.|School of Biological Sciences, Victoria University of Wellington, Wellington 6140, New Zealand. david.ackerley@vuw.ac.nz.
authors.forename: David F
authors.initials: DF
authors.lastname: Ackerley
authors.affiliation: The Clostridia Research Group, BBSRC/EPSRC Synthetic Biology Research Centre (SBRC) School of Life Sciences, University of Nottingham, Nottingham NG72RD, UK. nigel.minton@nottingham.ac.uk.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Minton
authors.affiliation: Maastro (Maastricht Radiation Oncology), GROW School for Oncology and Development Biology, Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands. philippe.lambin@maastro.nl.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lambin
authors.affiliation: Maastro (Maastricht Radiation Oncology), GROW School for Oncology and Development Biology, Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands. ludwig.dubois@maastrichtuniversity.nl.
authors.forename: Ludwig J
authors.initials: LJ
authors.lastname: Dubois
authors.affiliation: Maastro (Maastricht Radiation Oncology), GROW School for Oncology and Development Biology, Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands. jan.theys@maastrichtuniversity.nl.
authors.forename: Jan
authors.initials: J
authors.lastname: Theys
authors.affiliation: Translational Therapeutics Team, Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland 1023, New Zealand. j.smaill@auckland.ac.nz.|Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, University of Auckland, Auckland 1023, New Zealand. j.smaill@auckland.ac.nz.
authors.forename: Jeff B
authors.initials: JB
authors.lastname: Smaill
authors.affiliation: Translational Therapeutics Team, Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Auckland 1023, New Zealand. a.patterson@auckland.ac.nz.|Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, University of Auckland, Auckland 1023, New Zealand. a.patterson@auckland.ac.nz.
authors.forename: Adam V
authors.initials: AV
authors.lastname: Patterson
keywords: Clostridium; cancer; gene therapy; imaging; immunotherapy; prodrug; radiotherapy