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Prodrug-activated gene therapy: involvement of an immunological component in the "bystander effect"
1Department of Surgery, Royal Liverpool University Hospital, England.
Abstract:
The integration and expression of the herpes simplex virus type 1 thymidine kinase (HSV1-TK) gene in localized tumors results in tumor regression after the administration of the specific nucleoside analogue ganciclovir (GCV). Although only 10% to 20% of the tumor cells take up the HSV1-TK gene, the neighboring cells also die, a phenomenon termed "bystander effect.". In the present study, coinjection of the MC26 mouse colon carcinoma cell line and the HSV1-TK expressing retroviral packaging cell line followed after 7 days by the intraperitoneal administration of GCV resulted in almost total tumor regression in the immunocompetent BALB/c mice but not in immunocompromised athymic BALB/c mice. This suggested a strong cell-mediated immune component to the bystander effect.
Insights
Gene therapy using herpes simplex virus type 1 thymidine kinase (HSV1-TK) and ganciclovir (GCV) caused tumor regression. The bystander effect, where neighboring cells die, was significantly enhanced by the immune system in immunocompetent mice.
Area of Science:
- Oncology
- Gene Therapy
- Immunology
Background:
- Herpes simplex virus type 1 thymidine kinase (HSV1-TK) gene therapy with ganciclovir (GCV) induces tumor regression.
- The bystander effect, where HSV1-TK-expressing cells induce death in neighboring tumor cells, is crucial for this therapy.
Purpose of the Study:
- To investigate the role of the immune system in the bystander effect of HSV1-TK/GCV gene therapy.
- To evaluate the efficacy of HSV1-TK/GCV therapy in immunocompetent versus immunocompromised models.
Main Methods:
- Coinjection of MC26 mouse colon carcinoma cells and HSV1-TK retroviral packaging cells.
- Intraperitoneal administration of GCV 7 days post-injection.
- Comparison of tumor regression in immunocompetent BALB/c and athymic BALB/c mice.
Main Results:
- Almost complete tumor regression was observed in immunocompetent BALB/c mice.
- Tumor regression was not observed in immunocompromised athymic BALB/c mice.
- This indicates a significant immune-mediated component to the bystander effect.
Conclusions:
- The bystander effect in HSV1-TK/GCV gene therapy is strongly dependent on a functional cell-mediated immune response.
- This finding highlights the potential for combining gene therapy with immunomodulatory strategies for enhanced cancer treatment.