Systemic gene therapy of murine melanoma using tissue specific expression of the HSVtk gene involves an immune component

Richard Geoffrey Vile, J. Arly Nelson, Simon Castleden, Heung Chong, Ian R. Hart

Research output: Contribution to journalArticle

317 Citations (Scopus)

Abstract

Previously we have demonstrated safe and effective transfer of the HSVtk cytotoxic gene to primary murine melanoma tumors by direct injection of plasmid and retroviral vectors in which the HSVtk gene is driven by the tissue-specific tyrosinase promoter. However, for general clinical application such forms of therapy should, ideally, be effective against disseminated metastases. We report here that the number of recently established lung metastases of B16 melanoma in C57BL mice treated with ganciclovir is reduced compared to controls after multiple i.v. administrations of high titer retroviral supernatant encoding the HSVtk gene, but not after administration of liposome-complexed plasmid DNA. Using polymerase chain reaction analysis, integration of the provirus was observed in metastasis-bearing lungs (4 of 6 mice) and in the spleens of some ganciclovir-treated animals (2 of 6 mice) but not in the testes, brain, heart, liver, or kidney. The reduction in the number of experimental metastases in C57BL mice exceeded the anticipated extent of transduction of tumor cells, which is indicative of a marked bystander effect. This magnitude of reduction was not observed in immunodeficient athymic mice, suggesting that the immune system plays some part in the bystander effect. In support of these data, we show that, whereas the parental tumor cells are only poorly immunogenic, an effective antitumor immune response is generated following the killing of neoplastic cells in vivo as a result of treatment with ganciclovir. These effects may be responsible for augmenting the efficacy of retroviral infection. The combination of local cell killing by the HSVtk/ganciclovir system and the induction of antitumor immunity suggests new opportunities for the design of vectors for the gene therapy of cancer.

Original languageEnglish (US)
Pages (from-to)6228-6234
Number of pages7
JournalCancer Research
Volume54
Issue number23
StatePublished - Dec 1 1994
Externally publishedYes

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Ganciclovir
Genetic Therapy
Melanoma
Bystander Effect
Neoplasm Metastasis
Gene Expression
Inbred C57BL Mouse
Neoplasms
Plasmids
Virus Integration
Genes
Lung
Experimental Melanomas
Monophenol Monooxygenase
Nude Mice
Liposomes
Testis
Immune System
Immunity
Spleen

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Systemic gene therapy of murine melanoma using tissue specific expression of the HSVtk gene involves an immune component. / Vile, Richard Geoffrey; Nelson, J. Arly; Castleden, Simon; Chong, Heung; Hart, Ian R.

In: Cancer Research, Vol. 54, No. 23, 01.12.1994, p. 6228-6234.

Research output: Contribution to journalArticle

Vile, Richard Geoffrey ; Nelson, J. Arly ; Castleden, Simon ; Chong, Heung ; Hart, Ian R. / Systemic gene therapy of murine melanoma using tissue specific expression of the HSVtk gene involves an immune component. In: Cancer Research. 1994 ; Vol. 54, No. 23. pp. 6228-6234.
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