- 期刊
A DNA Cancer Vaccine Approach and a Combinatorial Cytokine Gene Therapy Approach for Murine Tumor Systems
並列摘要
Two cancer gene therapy approaches were taken in the recent work of my laboratories:I.) a gp100DNA cancer vaccine strategy for mouse melanoma, and 11)a combinatorial cytokine gene therapy strategy for mouse mammary tumors. I) DNA vaccination by particle-mediated gene delivery was used to immunize mice against melanoma. Mice were skin transfected with a cDNA expression vector coding for the human melanoma-associated antigen gp100. Murine B16 melanoma, stably transfected with human gp100 cDNA, was used as a tumor model. Particle-mediated delivery and expression of gp100 cDNA in the skin of naive mice resulted in significant tumor protection from subsequent tumor challenge. In comparison, co-delivery of granulocyte macrophage colony-stimulating factor (GM-CSF) cDNA together with gp100 cDNA consistently resulted in a significantly greater level of protection from tumor challenge. The inclusion of GM-CSI’ cDNS with the gp100 cDNA vaccine also allowed a drastic reduction in the gp100 cDNA dose required for antitumor efficacy, to as little as 62.5 ng per vaccination. Tumor protection induced by the gp100+GM-CSF gene combination was shown as T cell-mediated. This DNA cancer vaccine was also given to mice bearing established (7 day-old) tumors, and it resulted in a significant suppression of tumor growth and extended survival in test animals. These results indicate that inclusion of GM-CSF cDNA can augment the efficacy of gene gun-mediated vaccination with gp100 cDNA, and may warrant testing as a cancer vaccine strategy for human melanoma. II) Evaluated by many clinical investigators, cytokine therapy is considered as a promising approach for treating advanced forms of cancers, including breast cancer, because it can be directed at eradication of both the primary tumor and its metastases via activation of an antitumor immunity. We showed in our recent studies that a gene gun-mediated IL-12 gene therapy protocol were effective against two mouse mammary tumor systems, (the moderate immunogenic TS/A and the none or minimally immunogeneic 4T1 tumors). The key findings are :1) This IL-12 gene therapy protocol for the non-immunogenic 4T I adenocarcinoma does not significantly affect the growth of the primary tumor, but can significantly reduce metastasis into the lungs; 2) The observed anti-metastatic effect of IL-12 gene therapy against the 4T1 tumor apparently did not involve T-cells, but appeared to involve NK cells and IFN-g;3) Codelivery of a combination of IL-12, pro- IL-18 and IL-Ib converting enzyme(ICE) cDNA resulted in a synergistic, significantly enhanced inhibition of the growth of TS/A tumors; and 4) The IL-12, pro- IL-18 and ICE combinational gene therapy resulted in high level of IFN-g induction in vitro and in vivo, and was CD8+ cell dependent. These two approaches are being further evaluated for potential application to gene therapy of specific human cancers.