Overview of Retroviral Transduction of HSV-TK Gene in the Gene Suicide Therapy for Glioblastoma Multiform

Glioblastoma Multiform (GB) is the most malignant tumor of the brain. The treatment of GBM is a challenging task worldwide, and the prognosis of GBM remains poor, thus demanding the research of new and improved therapies. One new approach in treating GBM is through the transduction of the Herpes simplex Virus Thymidine Kinase (HSV-TK) gene, followed by ganciclovir (GCV) administration. During GBM treatment, the HSV-TK gene is first delivered into the host by retroviruses, one of the most commonly used vectors in said therapy due to their ability to selectively modify actively dividing cancer cells. Following the expression of HSV-TK, the HSV-TK enzyme catalyzes the phosphorylation of GCV into a cytotoxic metabolite, leading to the apoptosis of the target cell. Moreover, a phenomenon observed in cancer cells during gene suicide therapy named the"bystander effect" further enhanced CV cytotoxicity. Said effect enables the transfer of GCV-3P to surrounding cancer cells without HSV-TK transduction and expression, elevating cytotoxic effects throughout the tumor. However, due to the heterogeneous nature of GBM, relapse of the tumor is almost certain after HSV-TK therapy. Additionally, tumor-associated macrophages in the tumor microenvironment (TME) of GBM further enhance treatment difficulty. Further research should go towards understanding the TME of GBM to personalize better and design more effective treatments.