Targeted gene therapy for cancer: herpes simplex virus thymidine kinase gene-mediated cell killing leads to anti-tumour immunity that can be augmented by co-expression of cytokines in the tumour cells

Vile, R. G.; Díaz, Rosa María; Castleden, Simon; Chong, Heung

doi:10.1042/bst0250717

Cited by 20 publications

(14 citation statements)

References 13 publications

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“…A substantial literature exists on ectopic HSV1tk expression in animal models and human cancer therapy clinical trials, because of the potential ability to use HSV1tk as a therapeutic modality to locally activate prodrug acycloguanosines to toxic molecules. [23][24][25] As a result, we know more about ectopic expression of this reporter gene than other systems. Because HSV1tk is a 'foreign' gene, HSV1tk protein may be immunogenic.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive, quantitative imaging in living animals of a mutant dopamine D2 receptor reporter gene in which ligand binding is uncoupled from signal transduction

Liang¹,

Satyamurthy²,

Barrio³

et al. 2001

Gene Ther

168

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Section: Discussionmentioning

confidence: 99%

Noninvasive, quantitative imaging in living animals of a mutant dopamine D2 receptor reporter gene in which ligand binding is uncoupled from signal transduction

Liang¹,

Satyamurthy²,

Barrio³

et al. 2001

Gene Ther

168

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“…39 The use of IL-2 and other cytokines in conjunction with HSVtk has also shown promise. 22 Thus, future advances that improve selective gene transfer will increase the power of this emerging therapy as an adjunctive or even primary treatment of many human malignancies.…”

Section: Discussionmentioning

confidence: 99%

“…24 Furthermore, co-expression of HSVtk and immunomodulatory genes may enhance the tumoricidal response in vivo. 22 In the present study, we hypothesized that human osteosarcoma in vitro and in athymic mice would be susceptible to gene therapy with HSVtk and IL-2. Two osteosarcoma cell lines, MNNG (a human osteosarcoma) and MLM (a human-derived osteosarcoma metastatic to murine lung), were transduced in vitro with the HSVtk, IL-2, or ␤-galactosidase (␤-gal) gene.…”

mentioning

confidence: 95%

Bystander-mediated regression of osteosarcoma via retroviral transfer of the herpes simplex virus thymidine kinase and human interleukin-2 genes

2000

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Current treatment of osteosarcoma produces disappointing outcomes, and innovative therapies must be investigated. We have used retroviral vectors to transfer the herpes simplex virus thymidine kinase (HSVtk) and interleukin-2 genes to human osteosarcoma cells. Each gene was stably transduced and expressed; the HSVtk gene effectively conferred ganciclovir (GCV) susceptibility to transduced cells. A strong bystander effect was observed in vitro, whereby nontransduced tumor cells in proximity to transduced cells acquired susceptibility to GCV killing. Human osteosarcoma cells were used to develop a series of experiments in athymic nude mice to treat experimental osteosarcoma. Subcutaneously implanted mixtures of tumor cells and HSVtk vector producer cells developed into tumors that completely regressed upon administration of GCV. Subcutaneously implanted mixtures of transduced and wild-type cells showed a potent bystander effect upon administration of GCV, with complete tumor ablation when as little as 10% of the cells were HSVtk ϩ . A significant (P Ͻ .05) antitumoral response was seen against primary tumors composed of unmodified cells when a secondary tumor of transduced cells was implanted at a distance of 1 cm, suggesting a diffusible bystander factor. The presence of interleukin-2-transduced cells improved the efficacy of treatment. A significant (P Ͻ .03) antitumoral response was seen in the treatment of established osteosarcomas by the injection of HSVtk vector producer cells.

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“…Even though our animal model did not allow a thorough evaluation of the immune response, our in vivo results showed that GCV treatment of 50% transduced tumors led to a growth inhibition similar to the inhibition obtained in 100% infected tumors. The use of a cytokine gene besides a suicide gene allows the amplification of the antitumor effect by further stimulating immune-mediated rejection of cancer cells (13). Several in vivo studies in animal models of cancer demonstrated enhanced tumor cell killing with combined suicide and cytokine gene therapy (13 -18).…”

Section: Discussionmentioning

confidence: 99%

Gene therapy of thyroid cancer via retrovirally-driven combined expression of human interleukin-2 and herpes simplex virus thymidine kinase

Barzon

Bonaguro²,

Castagliuolo³

et al. 2003

European Journal of Endocrinology

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Objective and design: Based on our clinical experience with combined gene therapy of glioblastoma, we developed a retroviral vector expressing two therapeutic genes (i.e. thymidine kinase of herpes simplex virus, HSV-TK, and interleukin-2, IL-2 ) and evaluated its efficiency in vitro and in vivo. Methods: Expression of therapeutic genes in transduced thyroid carcinoma cells was analyzed by realtime RT-PCR. Ganciclovir sensitivity of infected cells was assessed in vitro in thyroid carcinoma cell lines and in vivo in nude mice bearing xenografted thyroid cancers. The combined effect of IL-2/ HSV-TK was compared with the effect of IL-2 alone. Results: Expression of therapeutic genes was higher in differentiated than in anaplastic thyroid carcinoma cells. Ganciclovir treatment led to dose-and time-dependent killing of transduced cells in vitro. A bystander effect was demonstrated by using mixtures of infected and non-infected cells. In vivo studies showed a significant reduction of growth and the presence of an inflammatory infiltrate in transduced thyroid tumors expressing IL-2 alone, as compared with non-infected tumors. By using the retroviral vector expressing IL-2/HSV-TK, treatment with ganciclovir led to complete eradication of anaplastic tumors and a . 80% reduction of the size of differentiated thyroid carcinomas. Histological analysis of tumor specimens showed extensive necrosis and inflammatory cell infiltrates. The combination of IL-2/HSV-TK plus ganciclovir was significantly more efficient than IL-2 alone in eradicating tumor masses. The bystander effect was also obtained in vivo.Conclusions: These findings demonstrate the feasibility and efficiency of a combined immunomodulating and suicide gene therapy approach for thyroid carcinomas.

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Targeted gene therapy for cancer: herpes simplex virus thymidine kinase gene-mediated cell killing leads to anti-tumour immunity that can be augmented by co-expression of cytokines in the tumour cells

Cited by 20 publications

References 13 publications

Noninvasive, quantitative imaging in living animals of a mutant dopamine D2 receptor reporter gene in which ligand binding is uncoupled from signal transduction

Noninvasive, quantitative imaging in living animals of a mutant dopamine D2 receptor reporter gene in which ligand binding is uncoupled from signal transduction

Bystander-mediated regression of osteosarcoma via retroviral transfer of the herpes simplex virus thymidine kinase and human interleukin-2 genes

Gene therapy of thyroid cancer via retrovirally-driven combined expression of human interleukin-2 and herpes simplex virus thymidine kinase

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