Tuberc Respir Dis.  2001 Aug;51(2):135-146. 10.4046/trd.2001.51.2.135.

Combination Gene Therapy of Herpes Simplex Virus Thymidine Kinase and Cytokines in Lung Cancer

• Kim G
• Park KH
• Seol JY
• Yoo CG
• Lee CT
• Kim YW
• Han SK
• Shim YS

• KMID: 2318345
• DOI: http://doi.org/10.4046/trd.2001.51.2.135

Abstract

BACKGROUND
One of the important mechanisms responsible for a tumor escaping the immune response is an absence of the tumor associated antigen (TAA) on the cancer cell surface. To overcome this, combination gene therapy using a herpes simplex thymidine kinase (HSTK) gene, prototype of drug sensitizing gene, was conducted to enhance TAA release by cell destruction, as well as the cytokine genes for immune cell attraction.
METHODS
We investigated whether or not transduction with the adenovirus-HSTK (Ad-HSTK) enhanced the sensitivity of Lewis lung carcinoma (LLC) to ganciclovir (GCV) and induced a bystander effect. A Tumor vaccine trial was performed using LLC with ad-HSTK ±ad-GM-CSF±ad-IL-2 to determine if they exhibit some antitumor effect on established lung cancer xenografts.
RESULTS
LLC with ad-HSTK revealed a much higher sensitivity to ganciclovir (GCV). LLC transduced with ad-HSTK and/or ad-IL-2, ad-GM-CSF showed a lower in vivo tumorigenicity. In the treatment experiment, vaccination with LLC transduced with ad-HSTK, ad-IL-2, or ad-GM-CSF alone modestly suppressed the growth of an established tumor. Combined transduction with HSTK and GM-CSF induced stronger growth suppression of a established lung cancer, while HSTK and IL-2 combination transduction did not have any antitumor effect on individual transduction. Vaccination with LLC-HSTK-GM-CSF increased the infiltration of dendritic cells in the spleen.
CONCLUSION
It was concluded that a tumor vaccine transduced with HSTK and GM-CSF induces strong antitumor immunity by activating the dendritic cells.

Keyword

Gene therapy; Herpes simplex virus thymidine kinase; IL-2; GM-CSF; Adenovirus; Dendritic cell

MeSH Terms

Adenoviridae
Animals
Bystander Effect
Carcinoma, Lewis Lung
Cytokines*
Dendritic Cells
Ganciclovir
Genetic Therapy*
Granulocyte-Macrophage Colony-Stimulating Factor
Herpes Simplex*
Heterografts
Interleukin-2
Lung Neoplasms*
Lung*
Phosphotransferases*
Simplexvirus*
Spleen
Thymidine Kinase
United Nations
Vaccination
Cytokines
Ganciclovir
Granulocyte-Macrophage Colony-Stimulating Factor
Interleukin-2
Phosphotransferases
Thymidine Kinase