This investigational new drug application describes a proposed phase I/II study designed to
      assess the safety and efficacy of AdV-tk gene therapy in combination with standard
      brachytherapy for patients with locally recurrent prostate cancer after having failed
      radiation as a primary treatment with or without minimal metastasis. These patients do not
      have any standard treatment that has been demonstrated to have a high degree of efficacy in
      eradicating the tumor with a reasonable degree of safety. Thus, the potential risks
      associated with the use of gene therapy in this group would appear reasonable. This
      application is for use of a replication defective adenovirus vector (ADV/RSV-tk) delivering
      the HSV-tk gene as a biologic vector for gene therapy.

      Direct introduction of therapeutic genes into malignant cells in vivo may provide an
      effective treatment of solid tumors such as prostate cancer. The herpes simplex virus
      thymidine kinase (HSV-tk) gene codes for an enzyme which phosphorylates the nucleoside analog
      ganciclovir (GCV) into an intermediate that is incorporated into newly synthesized DNA and
      terminates further replication, leading to cell death. Since normal mammalian cells do not
      possess this enzyme, cytotoxicity depends on the successful introduction and expression of
      the HSV-tk gene, phosphorylation of ganciclovir and synthesis of DNA. Non-dividing cells may
      express HSV-tk and phosphorylate ganciclovir but are not harmed since they do not synthesize
      DNA. This approach is especially suitable for the treatment of tumors where rapidly dividing
      tumor cells are adjacent to tissues made up largely of non-proliferating cells. Using human
      and animal models for prostate cancer we have demonstrated that adenovirus-mediated transfer
      of the HSV-tk gene resulted in sensitivity to ganciclovir in vitro and growth suppression of
      mouse prostate cancer in vivo.