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Combination gene therapy using multiple immunomodulatory genes transferred by a defective infectious single-cycle herpes virus in squamous cell cancer

 Se-Heon Kim  ;  John F. Carew  ;  David A. Kooby  ;  John Shields  ;  Claire Entwisle  ;  Snehal Patel  ;  Jatin P. Shah  ;  Yuman Fong 
 Cancer Gene Therapy, Vol.7(9) : 1279-1285, 2000 
Journal Title
Issue Date
Animals ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cancer Vaccines/genetics ; Cancer Vaccines/immunology ; Defective Viruses ; Disease-Free Survival ; Flow Cytometry ; Gene Transfer Techniques ; Genetic Therapy/methods* ; Genetic Vectors ; Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis ; Granulocyte-Macrophage Colony-Stimulating Factor/genetics* ; Herpesvirus 2 ; Human/genetics* ; Humans ; Interleukin-2/biosynthesis ; Interleukin-2/genetics* ; Mice ; Mice, Inbred C3H ; Neoplasms, Squamous Cell/metabolism ; Neoplasms, Squamous Cell/therapy* ; Neoplasms, Squamous Cell/virology ; Tumor Cells, Cultured ; Virus Replication
Squamous cell cancer ; gene therapy ; tumor vaccine ; defective infectious single-cycle virus ; granulocyte-macrophage colony-stimulating factor
Herpes simplex type 2-defective infectious single-cycle (DISC) viruses are attenuated viruses that were originally produced as viral vaccines; however, these viruses are also efficient gene transfer vehicles. The main goals of this study were to examine determinants of the gene transfer by using DISC virus for squamous cancer and to evaluate the antitumoral efficacy of vaccination with tumor cells modified by DISC viruses carrying a combination of immunomodulatory genes (interleukin-2 (IL-2), granulocyte-macrophage colony-stimulating factor (GM-CSF), B7-1) in a model of squamous cell cancer (SCCVII) in C3H/HeJ mice. SCCVII cells transduced by DISC viruses (multiplicity of infection of 10) carrying the IL-2 or GM-CSF gene produced nanogram quantities of IL-2 or GM-CSF per 10(6) cells. Irradiated (5,000 cGy, 10,000 cGy) cells secreted levels of GM-CSF or IL-2 that were comparable with nonirradiated cells. In vivo vaccination using tumor cells transduced ex vivo with DISC-IL2 or DISC-GMCSF resulted in protection against subsequent tumor challenge (P < .01), with DISC-GMCSF-transduced, irradiated tumor cells showing the greatest effects (P < .001). Marked growth arrest also was noted in established tumors after direct injection of DISC-GMCSF (P < .001). These data demonstrate that (a) DISC virus is capable of efficient gene transfer, (b) GM-CSF-secreting genetically modified tumor vaccine protects against tumor cell challenge and suppresses tumor growth, and (c) intratumoral injection of DISC-GMCSF significantly suppresses the growth of established tumors. These results not only confirm clinically relevant gene transfer but also demonstrate that the gene transfer is an effective anti-cancer therapy.
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1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Se Heon(김세헌)
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