Tumor killing using the HSV-tk suicide gene

The Herpes Simplex virus thymidine kinase gene (HSV-tk) has been widely used as a suicide gene in cancer gene therapy. Since the f irst demonstration of the abil ity of HSV-tk gene modified tumor cells to generate a bystander effect, a number of clinical trials have been initiated to treat human cancers. However, the mechanism of the HSV-tk mediated bystander tumor kil l ing has remained controversial and i s under intense investigation. The present report discusses the various mechanisms proposed by which the HSV-tk mediated bystander tumor killing occurs and highlights the importance of the host immune system in mediating the tumor killing. In addition, the present report also demonstrates that the initial tumor killing results in an inflammatory response leading to a cytokine cascade. This subsequently leads to an immune response result ing in an inf lux of macrophages and tumor infiltrating lymphocytes. Final ly , strategies to augment the HSV-tk mediated bystander tumor killing by immunization are discussed and conclude with potential pitfalls of using HSV-tk/GCV system in a clinical setting.