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.

Keywords: Clostridium; cancer; gene therapy; imaging; immunotherapy; prodrug; radiotherapy.

Figure 1

Cancer patients receive “armed” C. sporogenes spores which are able to germinate and colonise necrotic regions of their tumour.

Figure 2

Key (pre)clinical steps in clostridial use and development. CDEPT, Clostridium Directed Enzyme Prodrug Therapy.

Figure 3

Expression of therapeutic transgenes confers new properties to the bacteria. (A) Use of a Type I bacterial nitroreductase has the potential to provide multi-functional features including conditional cytotoxicity, positron emission tomography (PET) imaging capability, and antibiotic hypersensitivity, as discussed previously by Williams and colleagues [60]; (B) Use of antibody or cytokine expression to target the tumour microenvironment.