A novel cancer vaccine strategy with combined IL-18 and HSV-TK gene therapy driven by the hTERT promoter in a murine colorectal cancer model.

Abstract

A therapeutic vaccine against minimal residual cancer cells is needed for the treatment of patients with colorectal cancer. Several gene therapy studies have revealed that the combination of a suicide gene and cytokine gene might induce effective antitumor immunity. In this study, we constructed an interleukin (IL)-18 and herpes simplex virus-thymidine kinase (HSV-TK) expression vector driven by the human telomerase reverse transcriptase (hTERT) promoter to study the efficacy of combination gene therapy with IL-18 and the HSV-TK suicide gene. Low immunogenic colon 26 cells were used for transfection and inoculation into syngeneic BALB/c mice. Large established tumors of colon 26 transfectants expressing IL-18 and HSV-TK driven by the hTERT promoter were completely eradicated after GCV administration in syngeneic BALB/c mice. Immunohistochemical analysis at the tumor rejection sites revealed enormous infiltrations of CD8+ T lymphocytes as well as CD4+ T lymphocytes and CD11b+ monocytes. Moreover, established distant tumors were completely eradicated by vaccination with the IL-18 and HSV-TK transfectants in combination with GCV. These data suggest that the IL-18 and suicide gene therapy can elicit antitumor specific immunity. In conclusion, gene therapy with IL-18 and HSV-TK plasmid vector driven by the hTERT promoter may be useful for cancer vaccination.

• Authors: Kosuke Higashi, Shoichi Hazama, Atsuhiro Araki, Kiyoshi Yoshimura, Norio Iizuka, Shigefumi Yoshino, Takafumi Noma, Masaaki Oka
• Journal: International journal of oncology (Int J Oncol) Vol. 45 Issue 4 Pg. 1412-20 (Oct 2014) ISSN: 1791-2423 [Electronic] Greece
• PMID: 25051201 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cancer Vaccines
• Interleukin-18
• Viral Proteins
• Thymidine Kinase
• TERT protein, human
• Telomerase
• Ganciclovir

Topics

• Animals
• Cancer Vaccines (administration & dosage, genetics)
• Cell Line, Tumor
• Colorectal Neoplasms (genetics, immunology, metabolism, therapy)
• Female
• Ganciclovir (administration & dosage, therapeutic use)
• Genes, Transgenic, Suicide
• Genetic Therapy (methods)
• Genetic Vectors (genetics)
• Humans
• Interleukin-18 (administration & dosage, genetics)
• Mice
• Mice, Inbred BALB C
• Neoplasms, Experimental
• Promoter Regions, Genetic
• Simplexvirus (enzymology, genetics)
• Telomerase (genetics)
• Thymidine Kinase (administration & dosage, genetics)
• Viral Proteins (genetics, metabolism)