title: IL-15/sIL-15Rα gene transfer suppresses Lewis lung cancer growth in the lungs, liver and kidneys.
abstract: Nearly 40% of people with lung cancer have tumor growth in other organs at the time of diagnosis. Current treatment strategies for patients with late-stage lung cancer are primarily palliative and only showed modest efficacy. The current study takes advantage of the hydrodynamic gene delivery technique to evaluate the antitumor activity of interleukin (IL)-15/sIL-15Rα on lung tumors growing in the lungs, liver and kidneys. We demonstrate that hydrodynamic tail vein injection of 2 μg of AG209 DP muIL-15sRα+IL-15 plasmid resulted in serum IL-15/sIL-15Rα reaching a peak level of ~10 μg ml(-1) 1 day after the injection and gradually declined to ~5 ng ml(-1) within 3 days. Quantitative PCR analysis revealed that overexpression of IL-15/sIL-15Rα induced the activation of natural killer and T cells, evidenced by increased mRNA levels of marker genes including granzyme B, perforin, Ifn-γ, T-bet and Cd8 in the lungs, liver and kidneys. Importantly, transfer of the Il-15/sIl-15Rα gene alone, or in combination with gemcitabine chemotherapy, significantly inhibited the tumor growth in these three organs and prolonged median survival time of treated mice by 1.7- and 3.3-fold, respectively. The therapeutic benefits are principally blockade and elimination of tumor growth in the liver and kidneys. Taken together, these results suggest that IL-15/sIL-15Rα-based gene therapy could be an effective approach to treat late-stage lung cancer with metastases in other organs.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Liu
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D016827:CD8 Antigens / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics*; D007680:Kidney Neoplasms / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism; D053647:Receptors, Interleukin-15 / Q000235:genetics; D015996:Survival Rate; D020825:T-Box Domain Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D000093542:Gemcitabine; D000098815:T-bet Transcription Factor
chemical_list: D000964:Antimetabolites, Antineoplastic; D016827:CD8 Antigens; C000611649:IFNG protein, mouse; C508025:Il15ra protein, mouse; D019409:Interleukin-15; D052899:Pore Forming Cytotoxic Proteins; D053647:Receptors, Interleukin-15; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C483886:perforin, mouse; D003841:Deoxycytidine; D007371:Interferon-gamma; D053804:Granzymes; C509214:Gzmb protein, mouse; D000093542:Gemcitabine