Non-viral immune electrogene therapy induces potent antitumour responses and has a curative effect in murine colon adenocarcinoma and melanoma cancer models.
Antitumour efficacy of electroporated pEEV, coding for granulocyte-macrophage colony-stimulating factor and the B7-1 costimulatory immune molecule (pEEVGmCSF-b7.1) in growing solid tumours, was investigated and compared with a standard plasmid. Application of pEEVGmCSF-b7.1 led to complete tumour regression in 66% of CT26-treated tumours and 100% in the B16F10-treated tumours at day 150 post-treatment. pEEVGmCSF-b7.1 treatment was found to significantly enhance levels of both innate and adaptive immune populations in tumour and systemic sites, which corresponded to significantly increased tissue levels of proinflammatory cytokines including interferon-γ (IFN-γ) and interleukin-12 (IL-12). In contrast, pEEVGmCSF-b7.1 treatment significantly reduced the T-regulatory populations and also the anti-inflammatory cytokine IL-10. Upon further characterisation of functional immune responses, we observed a significant increase in cytotoxic (CD107a+) and IFN-γ-producing natural killer cells and also significantly more in IL-12-producing B cells. Importantly, splenocytes isolated from pEEVGmCSF-b7.1-treated 'cured' mice were tumour-specific and afforded significant protection in a tumour rechallenge model (Winn assay). Our data indicate that electroimmunogene therapy with the non-viral pEEVGmCSF-b7.1 is able to induce potent and durable antitumour immune responses that significantly reduce primary and also secondary tumour growth, and thus represents a solid therapeutic platform for pursuing future clinical trials.
Cork Cancer Research Centre, Leslie C Quick Laboratory, BioSciences Institute, University College Cork, Cork, Ireland.
P F
PF
Forde
Norwich Medical School, University of East Anglia, Norwich, UK.
L J
LJ
Hall
Cork Cancer Research Centre, Leslie C Quick Laboratory, BioSciences Institute, University College Cork, Cork, Ireland.
M
M
de Kruijf
Cork Cancer Research Centre, Leslie C Quick Laboratory, BioSciences Institute, University College Cork, Cork, Ireland.
M G
MG
Bourke
Cork Cancer Research Centre, Leslie C Quick Laboratory, BioSciences Institute, University College Cork, Cork, Ireland.
T
T
Doddy
Cork Cancer Research Centre, Leslie C Quick Laboratory, BioSciences Institute, University College Cork, Cork, Ireland.
M
M
Sadadcharam
Cork Cancer Research Centre, Leslie C Quick Laboratory, BioSciences Institute, University College Cork, Cork, Ireland.
D M
DM
Soden
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D018274:Electroporation; D005260:Female; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D007156:Immunologic Memory; D007694:Killer Cells, Natural / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013154:Spleen / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014162:Transfection
D016178:Granulocyte-Macrophage Colony-Stimulating Factor