Treatment of rat gliosarcoma brain tumors by HSV-based multigene therapy combined with radiosurgery

Abstract

Our laboratory has employed replication-defective herpes simplex virus type 1 gene transfer vectors for treatment of animal models of human malignant glioblastoma. The base vectors were defective for the immediate early (IE) genes ICP4, ICP27, and ICP22 but expressed the IE gene ICP0, which can arrest tumor cell division, and an IE thymidine kinase (α-tk) gene construct that mediates suicide gene therapy (SGT) in the presence of ganciclovir (GCV). Previously, we reported that SGT using ICP0/α-tk vectors in nude mouse models of glioblastoma was improved by coexpression of the gap-junction-forming protein connexin43 (Cx43) or human tumor necrosis factor α (TNFα). We also showed that further gains in therapeutic outcome could be achieved by combining TNFα-enhanced SGT with gamma-knife radiosurgery (GKR). To expand these observations, we have first repeated these studies in immunocompetent rats with brain tumors derived from implanted 9L gliosarcoma cells and second compared the most efficient vector from this study with a new recombinant vector, NUREL-C2, which expressed both TNFα and Cx43 along with ICP0 and α-tk. Results from the first part indicated that our ICP0/α-tk/TNFα vector in combination with GKR provides an effective therapy although this treatment was not statistically better than GKR combined with the ICP0/α-tk/Cx43 vector. Our observations in the second part suggested that NUREL-C2 may be more effective than the ICP0/α-tk/TNFα vector in combination treatments with GCV (P = 0.08) or GCV plus GKR (P = 0.10). GKR significantly enhanced the efficacy of NUREL-C2/GCV treatment (P = 0.02) as well as other virus/GCV treatments (P ≤ 0.05). Conversely, the efficacy of GKR was significantly improved by both the ICP0/α-tk/TNFα vector and NUREL-C2 in combination with GCV (P = 0.02 and P < 0.01, respectively). Together these results indicate that NUREL-C2 may be an attractive candidate for Phase I gene-therapy safety studies in patients with recurrent malignant glioblastoma.