Combining gene and immunotherapy for prostate cancer.
The nitroreductase (NR)/CB1954 enzyme prodrug system has given promising results in pre-clinical studies and is currently being assessed in phase I and II clinical trials in prostate cancer. Enhanced cell killing by apparent immune-mediated mechanisms has been shown in pancreatic and colorectal cancer models, by co-expressing murine granulocyte macrophage colony-stimulating factor (GM-CSF) with NR in a single replication deficient adenoviral vector. This consists of the CMV immediate early promotor driving expression of NR, with an internal ribosome entry site (IRES) and the gene for murine GM-CSF (mGM-CSF). To examine if similar enhancement of tumour cell killing could be produced in prostate cancer, the TRAMP model was chosen. Results illustrate that the combination of suicide gene therapy using NR and CB1954, with cytokine stimulation with mGM-CSF gives an improved response compared with either modality alone. The mechanism of this improved response is however likely to be non-immune based as it lacks a memory effect.
Young
J G
JG
Cancer Research UK Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK.
Green
N K
NK
Mautner
V
V
Searle
P F
PF
Young
L S
LS
James
N D
ND
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001388:Aziridines / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001711:Biotransformation; D003131:Combined Modality Therapy; D003673:Defective Viruses / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D005813:Genes, Synthetic; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000627:therapeutic use*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009601:Nitroreductases / Q000235:genetics / Q000378:metabolism*; D011355:Prodrugs / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011994:Recombinant Proteins; D013047:Specific Pathogen-Free Organisms
D000970:Antineoplastic Agents; D001388:Aziridines; D029968:Escherichia coli Proteins; D011355:Prodrugs; D011994:Recombinant Proteins; C100099:tretazicar; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C116053:NfsA protein, E coli; D009601:Nitroreductases