Limited Efficacy of the HSV-TK/GCV System for Gene Therapy of Malignant Gliomas and Perspectives for the Combined Transduction of the Interleukin-4 Gene

Abstract

The growth of U-87 or C6 gliomas co-implanted in nude mice with retroviral producer cells (VPC) expressing the herpes simplex virus-thymidine kinase (HSV-tk) gene is only partially impaired by treatment with ganciclovir (GCV). The effect of GCV is even less evident when C6 and VPC are co-implanted into the rat brain. Furthermore, tumors from C6 cells carrying the HSV-tk gene are not eradicated by GCV, although they remain sensitive to GCV when replated in vitro. These limits of the HSV-tk/GCV system in glioma gene therapy may be due to insufficient gene transfer and/or insufficient delivery of GCV to glioma cells. Combination of HSV-tk and one or more cytokines may improve the antitumor efficacy. Among cytokines, interleukin-4 (IL-4) has already been shown to be active against gliomas. In nude mice, GCV treatment inhibited tumor growth more effectively after co-injection of C6 cells with a mixture of VPC transducing IL-4 and HSV-tk genes than after co-injection with either IL-4 or HSV-tk VPC only. In immunocompetent Sprague-Dawley rats, co-injection of IL-4 VPC and C6 cells was also effective in inhibiting the growth of C6 brain tumors, 38% of the animals surviving for at least 2 months. Furthermore, increased and prolonged antitumor efficacy was obtained by transducing both IL-4 and HSV-tk genes. We used the herpes simplex virus-thymidine kinase/ganciclovir (HSV-tk/GCV) system to treat C6 or U-87 malignant gliomas implanted in rat brain or in nude mice and found that such treatment is hampered not only by a limited capacity for gene transfer but also by a limited delivery of GCV. These results suggest that other strategies should be used to complement such a system. Our data indicate that by combining the retrovirus-mediated transfer of the interleukin-4 (IL-4) gene to that of the HSV-tk gene a more effective limitation in the growth of malignant gliomas can be obtained in nude mice and that this antitumor effect is stronger and more prolonged in immunocompetent rats.