Gene therapy with GM-CSF, interleukin-4 and herpes simplex virus thymidine kinase shows strong antitumor effect on lung cancer.
BACKGROUND
Inadequate release of tumor antigens (TA) and a defective antigen presentation by dendritic cells (DC) are the major mechanisms for how tumor cells can escape the host immune surveillance.


METHODS
Combined gene therapy of herpes simplex virus thymidine kinase (Tk), GM-CSF and IL-4 via adenoviral vector was tested to solve these problems. After establishing wild-type Lewis lung carcinoma (LLC), vaccinations with LLC transduced with Tk +/- GM-CSF +/- IL-4 were performed.


RESULTS
The LLC-Tk and LLC-Tk-IL-4 vaccination groups failed to suppress the wild-type LLC growth. However, the LLC-Tk-GM-CSF group showed a delayed wild-type tumor growth and LLC-Tk-GM-CSF-IL-4 markedly suppressed tumor growth and increased the survival rate of mice. Immunohistochemistry of the spleen showed a dense infiltration of DCs in the mice treated with LLC-Tk-GM-CSF-IL-4.


CONCLUSIONS
Combined gene therapy with Tk-GM-CSF-IL-4 was effective in inducing antitumor immunity by enhancing the DC functions.
Park
Kyung-Ho
KH
Department of Internal Medicine, Seoul National University College of Medicine, Gene Therapy Laboratory of Clinical Research Institute, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, Korea.
Kim
Gyesu
G
Jang
Seung Hun
SH
Kim
Cheol Hyeon
CH
Kwon
Sung-Youn
SY
Yoo
Chul-Gyu
CG
Kim
Young Whan
YW
Kwon
Hee Chung
HC
Kim
Chang-Min
CM
Han
Sung Koo
SK
Shim
Young-Soo
YS
Lee
Choon-Taek
CT
D000818:Animals; D017951:Antigen Presentation; D000998:Antiviral Agents / Q000627:therapeutic use; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000628:therapy*; D003587:Cytomegalovirus / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D015774:Ganciclovir / Q000627:therapeutic use; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000502:physiology; D007157:Immunologic Surveillance; D007376:Interleukin-2 / Q000235:genetics / Q000502:physiology; D015847:Interleukin-4 / Q000235:genetics* / Q000502:physiology; D017921:Mastadenovirus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000502:physiology; D018139:Simplexvirus / Q000201:enzymology / Q000235:genetics*; D013154:Spleen / Q000276:immunology; D013937:Thymidine Kinase / Q000235:genetics* / Q000502:physiology; D014161:Transduction, Genetic; D019139:Tumor Escape; D014611:Vaccination; D014764:Viral Proteins / Q000235:genetics* / Q000502:physiology
D000998:Antiviral Agents; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013937:Thymidine Kinase; D015774:Ganciclovir