title: Cancer-targeted BikDD gene therapy elicits protective antitumor immunity against lung cancer.
abstract: Targeted cancer-specific gene therapy is a promising strategy for treating metastatic lung cancer, which is a leading cause of lung cancer-related deaths. Previously, we developed a cancer-targeted gene therapy expression system with high tumor specificity and strong activity that selectively induced lung cancer cell killing without affecting normal cells in immunocompromised mice. Here, we found this cancer-targeted gene therapy, SV-BikDD, composed of the survivin promoter in the VP16-GAL4-WPRE integrated systemic amplifier system to drive the apoptotic gene BikDD, not only caused cytotoxic effects in cancer cells but also elicited a cancer-specific cytotoxic T lymphocyte response to synergistically increase the therapeutic effect and further develop an effective systemic antitumoral immunity against rechallenges of tumorigenic dose of parental tumor cells inoculated at distant sites in immunocompetent mice. In addition, this cancer-targeted gene therapy does not elicit an immune response against normal tissues, but CMV-BikDD treatment does. The therapeutic vector could also induce proinflammatory cytokines to activate innate immunity and provide some benefits in antitumor gene therapy. Thus, this study provides a promising strategy with benefit of antitumoral immune response worthy of further development in clinical trials for treating lung cancer via cancer-targeted gene therapy.
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan.
authors.forename: Yuh-Pyng
authors.initials: YP
authors.lastname: Sher
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Liu
authors.forename: Chun-Mien
authors.initials: CM
authors.lastname: Chang
authors.forename: Shu-Pei
authors.initials: SP
authors.lastname: Lien
authors.forename: Chien-Hua
authors.initials: CH
authors.lastname: Chen
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Han
authors.forename: Long-Yuan
authors.initials: LY
authors.lastname: Li
authors.forename: Jin-Shing
authors.initials: JS
authors.lastname: Chen
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Wu
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D007113:Immunity, Innate / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D011401:Promoter Regions, Genetic / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D000077022:Survivin; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D047368:Tumor Burden / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C111741:Bik protein, mouse; C117749:Birc5 protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D051034:Inhibitor of Apoptosis Proteins; D024101:Mitochondrial Proteins; D050505:Mutant Proteins; D012097:Repressor Proteins; D000077022:Survivin