Long-Term Survival in a Rodent Model of Disseminated Brain Tumors by Combined Intrathecal Delivery of Herpes Vectors and Ganciclovir Treatment

Abstract

Brain tumors that have disseminated into cerebrospinal fluid (CSF) pathways are an unresolved therapeutic problem, especially in pediatric neurooncology. Here a gene therapy approach using the herpes simplex virus type 1 thymidine kinase (HSV-TK)/ganciclovir (GCV) paradigm was tested using an HSV vector in a rodent model of disseminated central nervous system tumors. 9L-gliosarcoma cells were implanted simultaneously into the brain and the CSF of syngeneic rats. Five days later, resulting intracerebral and leptomeningeal tumors were treated by intrathecal injection of a replication-conditional HSV vector. This vector was defective for the ribonucleotide reductase gene, but contained an intact HSV-tk gene. Systemic GCV treatment was started 2 days after vector application and continued for 14 days. Tumor-free, long-term survival (LTS) was achieved in 90% of the animals treated with this combined therapeutic approach, whereas only 30% LTS was found in animals that had received the vector alone and 10% LTS in untreated animals. This therapeutic response probably involves oncolytic, on-site replication of the vector, activation of GCV by a HSV-TK, and a strong immune response both to the vector and to 9L cells. Apparent vector-related mortality was observed in 20% of animals without subsequent GCV therapy, but no vector-related mortality was found when the animals were treated with GCV after vector application. Given the successful outcome of this experimental treatment and the apparent potential of GCV to control HSV-related toxicity, intrathecal application of HSV vectors combined with GCV treatment may be a promising approach for treatment of disseminated brain tumors.

Overview summary

Dissemination of tumor cells throughout the cerebrospinal fluid (CSF) pathways is prognostically unfavorable in pediatric brain tumors. Local therapeutic strategies are not sufficient to treat or prevent CSF metastases. Experimental gene therapy has the potential to effect a more systemic mode of action. Here, we present a modified gene therapy approach based on the herpes simplex virus type 1 thymidine kinase (HSV-TK)/ganciclovir (GCV) paradigm, which provides multifocal therapeutic potential by intrathecal gene delivery via a replication-conditional HSV vector. A marked increase in long-term survival was noted in a rodent combined model of intracerebral and CSF gliosarcoma tumors, which was accompanied, however, by vector-related toxic side effects. Although these side effects appeared to be reduced by GCV, safer HSV vectors will need to be generated to explore the high therapeutic potential of these vectors for human clinical brain tumor therapy.