Abstract
III. Scientific Abstract
This study will evaluate the safety and efficacy of in vivo gene transfer of the Herpes Simplex-thymidine kinase (HStk) gene using PA317/LTKOSN.2 vector producing cells (VPC) in patients with recurrent or refractory ovarian cancer. Insertion of the HStk gene into tumor cells confers a sensitivity to the anti-herpes drug ganciclovir (GCV). The HStk/GCV system induces a bystander effect and an anti-tumor immune response. HStk VPC have destroyed intraperitoneal tumors growing in animals. This selective destruction of growing tumors in situ is thought to result from the production of toxic GCV metabolites within the tumor. This procedure has resulted in the cure of experimental animals with limited toxicity. Therefore, we propose to apply this technique for the treatment of refractory or relapsed ovarian cancer.
Adult women (≥18 years) with recurrent or refractory ovarian cancer, will be evaluated for the extent and location(s) of their disease before being entered into the study. Patients will have a CT scan and peritonoscopy with biopsy to confirm the diagnosis. During peritonoscopy, eligible patients will have a Tenckhoff catheter placed. HStk VPC will be infused into the peritoneal space. Two weeks later, GCV will be administered at 5 mg/kg/dose IV b.i.d. for 14 days. Patients will only receive one cycle of therapy in this dose escalation protocol. After the completion of the course of GCV, the patient will then be followed at least every 4 weeks for the first 6 months and then at 2 to 6 month intervals. This protocol is related in principle to RAC approved protocols for the treatment of brain tumors in adults and children. This protocol is novel in the site of administration of the HStk VPC and the dose escalation schema.
IV. Nontechnical Abstract
We have investigated the possibility of transferring genes into tumor cells within the body. These genes change the tumor so that it becomes sensitive to a type of chemotherapy that is not toxic to normal parts of the body. These changes may also make the tumor more visible to the immune system. The gene we have selected is the Herpes Simplex-thymidine kinase (HStk) gene, one of many genes contained within the Herpes Simplex Virus. The Herpes simplex virus can be killed by a drug called Ganciclovir (GCV). By transferring the HStk gene into the tumor, using a disabled mouse virus called a vector, we can convert the tumor to be genetically like a herpes virus. The HStk-containing tumor can now be killed with GCV.
We have conducted experiments in mice with cancer cells growing throughout their abdomens. The direct injection of mouse cells producing HStk vectors into these mice, can eliminate all evidence of tumor growth. We now propose a trial for patients with ovarian cancer who have failed standard therapies. Patients will undergo surgery to place a plastic catheter into the abdomen and then receive an injection of HStk vector producing cells into the abdomen through the catheter. The patients will receive GCV by intravenous infusion for 2 weeks after the injection of the vector producing cells. Response to therapy will be assessed by X-ray studies and looking into the abdomen with a scope.
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