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Enhanced Antitumor Effect of Oncolytic Adenovirus Expressing Interleukin-12 and B7-1 in an Immunocompetent Murine Model

 Young-Sook Lee  ;  Joo-Hang Kim  ;  Kyung-Ju Choi  ;  Il-Kyu Choi  ;  Hoguen Kim  ;  Sungae Cho  ;  Byoung Chul Cho  ;  Chae-Ok Yun 
 CLINICAL CANCER RESEARCH, Vol.12(19) : 5859-5868, 2006 
Journal Title
Issue Date
Adenoviridae/genetics* ; Animals ; B7-1 Antigen/genetics ; B7-1 Antigen/immunology ; B7-1 Antigen/metabolism* ; Drug Therapy, Combination ; Gene Expression ; Genetic Therapy/methods* ; Genetic Vectors/administration & dosage ; Humans ; Interferon-gamma/metabolism ; Interleukin-12/genetics ; Interleukin-12/immunology ; Interleukin-12/metabolism* ; Male ; Melanoma, Experimental/immunology ; Melanoma, Experimental/therapy* ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Neoplasms/immunology ; Neoplasms/therapy* ; Oncolytic Virotherapy/methods* ; T-Lymphocytes/immunology ; Tumor Cells, Cultured ; Virus Replication/drug effects
PURPOSE: We investigated whether an armed viral platform, where lytic property of a viral infection is coupled to viral-mediated delivery of therapeutic genes, could increase the therapeutic potential of a viral-based therapy.
EXPERIMENTAL DESIGN: We generated interleukin (IL)-12-expressing oncolytic adenovirus (YKL-IL-12) and IL-12- and B7-1-expressing (YKL-IL12/B7) oncolytic adenovirus. Therapeutic efficacy of these newly engineered adenoviruses was then evaluated in vivo using an immunocompetent mouse bearing murine melanoma B16-F10 tumors. Overall survival was assessed with the Kaplan-Meier method. The induction of immune cell cytotoxicity was assessed by CTL assay, IFN-gamma enzyme-linked immunospot assay, and immunohistochemical studies.
RESULTS: YKL-IL12/B7 oncolytic adenovirus, expressing both IL-12 and B7-1, showed a higher incidence of complete tumor regression compared with the analogous oncolytic adenovirus, YKL-1, or IL-12-expressing, YKL-IL12. Significant survival advantage was also seen in response to YKL-IL12/B7. Moreover, IL-12 and IFN-gamma levels produced in tumors treated with YKL-IL12/B7 was significantly greater than those treated with YKL-IL12. The enhanced survival advantage was mediated by the induction of immune cell cytotoxicity. In agreement with these results, massive infiltration of CD4(+) and CD8(+) T cells into tissues surrounding the necrotic area of the tumor was observed following in situ delivery of YKL-IL12/B7.
CONCLUSION: Combination of oncolysis and the enhancement of antitumor immune response by oncolytic adenovirus expressing both IL-12 and B7-1 elicits potent antitumor effect and survival advantage.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Joo Hang(김주항)
Kim, Hogeun(김호근)
Yun, Chae Ok(윤채옥)
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