Gene Therapy for the Treatment of Brain Tumors Using Intra-Tumoral Transduction with the Thymidine Kinase Gene and Intravenous Ganciclovir. National Institutes of Health
Murine retroviral vectors can infect a wide variety of proliferating mammalian cell types (e.g. lymphocytes). Non-proliferating tissues (e.g. neurons) are not transduced by murine retroviral vectors. These findings suggest that this type of vector may be useful for the selective introduction of genes into growing tumors in the brain, since the tumor is essentially the only tissue that would integrate and express the vector genes. We investigated the possibility of in vivo transduction of growing brain tumors with the herpes simplex thymidine kinase (HS-tk) gene. Rats with a malignant brain tumor were given an intratumoral stereotaxic injection of murine fibroblasts that were producing a retroviral vector containing the herpes simplex thymidine kinase (HS-tk) gene or a control vector producer cell line containing the β-galactosidase gene. The animals were rested 5 days to allow time for the HS-tk retroviral vectors that were produced in situ to transduce the neighboring proliferating glioma. The animals were then treated with the anti-herpes drug ganciclovir (GCV). Gliomas injected with the HS-tk producer cells regressed completely with GCV therapy while the tumors injected with β-galactosidase producers had large tumors. Staining for β-galactosidase positive cells in control animal brain revealed transduction of 40–80% of the tumor cells without evidence of transduction of the surrounding normal brain tissue. No significant toxicity was observed in toxicity studies in mice, rats and non-human primates. Based upon these findings, we have proposed a human clinical trial to determine if the direct injection of the G1TkSvNa producer cell line into growing human brain tumors will regress with GCV therapy. The patient population consists of individuals with recurrent malignant tumors who have failed standard therapy for their primary or metastatic brain tumors. The expected survival of these patients is limited to weeks to a few months. We have investigated the possibility of transferring a gene into a growing brain tumor. The purpose is to make the tumor sensitive to a type of chemotherapy that is relatively non-toxic to the rest of the body. The gene we have selected is the Herpes Simplex thymidine kinase (HS-tk) gene. Herpes Simplex is virus that can be killed by a drug called ganciclovir. By tiansferring the HS-tk gene into the tumor, using a disabled virus called a “vector”, we then essentially convert the tumor to be like a herpes virus and now the tumor can be killed with ganciclovir. Experiments in rats have been shown that the direct injection of mouse cells producing a HS-tk vector into a growing brain tumor can result in complete destruction of the tumor with ganciclovir therapy. We found no evidence of spread of the virus to the normal brain tissue or to other parts of the body. Based upon these findings, we have proposed a human clinical trial to determine if the direct injection of the HS-tk producer cells into growing human brain tumors will regress with GCV therapy. The patient population consists of individuals who have failed standard therapy and have recurrent primary or metastatic brain tumors with an expected survival of weeks to a few months.