Introduction--translational research trends: urologic gene therapy.

Abstract

GENE THERAPY, a rapidly growing field of interest in the basic sciences, is a relatively new area of research and clinical application within urology. With increasing technological advances, the number of gene therapy-based clinical trials has increased dramatically. As such, translational research involving gene therapy for a variety of urologic diseases has also increased. In this issue, the contributors present a review of the proceedings from the First Meeting of Japanese Urological Association for Gene Therapy, held on November 20, 1999 in Okayama, Japan. An overview of the meeting was presented by the society’s first president, Dr. Kumon. A guest speaker, Dr. Asano, defined gene therapy translational research objectives and emphasized the importance of applying appropriate basic science concepts in selected preclinical models. He also stressed the careful design of good manufacturing principles and clinical trial indications, patient selection, and logistics. Specific urologic applications of gene therapy were also presented and discussed at the meeting. Gene therapy strategies can essentially be classified into three basic categories: (1) immune augmentation; (2) as a mode of delivery of cytotoxic agents; and (3) specific gene replacement. One of the earliest gene therapy strategies to augment the immune system attempted to deliver high concentrations of cytokines to localize the host immune response. Two basic cytokine delivery strategies are currently utilized: one is to vaccinate patients with tumor cells expressing a particular cytokine, and the other is to directly express cytokines within the tumor. Vaccination with cytokine-expressing tumor cells enhances the efficacy of tumor cell vaccination strategies in rodent models. The most widely utilized cytokine in current clinical trials is granulocyte-macrophage colony-stimulating factor (GM-CSF). Kawai et al., review the data of trials using GM-CSF expressing autologous tumor cells in renal cell carcinoma, malignant melanoma, and prostate cancer. Thus far, despite demonstrating histologic confirmation of host immune response at the sites of immunization, clinically evident tumoricidal responses of the in situ tumor are not yet evident. However, multiple variables need to be addressed before disregarding this approach as a viable gene therapy strategy. These variables include vaccination dosage and frequency as well as the in situ tumor burden at the time of vaccination. An alternative method to augment the host immune response with local cytokines is direct expression of the cytokine with the tumor itself. Nishitani et al. review cytokine gene therapy using naked DNA gene transfer techniques. They presented promising preliminary preclinical data using interleukin-12 (IL12) transfected in situ into subcutaneous renal cell carcinoma tumors in a murine model. One potential limitation of this strategy centers on efforts to ensure delivery of the cytokine gene into the tumor. In particular, in situ targeting of renal cell carcinoma cells versus normal kidney cells may present a clinical problem. This could be overcome if the cytokine gene could be expressed in a tumor-specific manner. Nonetheless, gene therapy immune augmentation is one of the most promising immunotherapy strategies. An alternative gene therapy strategy to target tumors is to use cytotoxic genes or viruses. Cytotoxic gene therapy primarily locally targets tumors but may also have bystander and/or immune-stimulating effects in surrounding cells. The most widely utilized cytotoxic gene is the herpes simplex virus thymidine kinase (HSV-TK) gene. The HSV-TK gene converts a nontoxic metabolite into a toxic metabolite, killing cells expressing the HSV-TK gene, and thus this strategy is aptly named “suicide” gene therapy. Nasu et al., review the usage of the HSV-TK gene in gene therapy trials. Tumor-specific expression of the HSV-TK gene may limit toxicity to normal tissues lacking HSV-TK expression. Shirakawa et al. presented data using tissue-specific expression of the HSV-TK gene using the prostate-specific antigen (PSA) and osteocalcin promoters. The PSA promoter restricts expression primarily to prostate tissues, whereas the osteocalcin promoter targets prostate cancer and bone metastasis. Preliminary data of their Phase I clinical trial, using adenovirus encoding the osteocalcin promoter directed expression of the HSV-TK gene, demonstrated this strategy could be used with minimal toxicity. Cytotoxic gene therapy also includes the usage of cytotoxic viruses that target rapidly dividing tumor cells. Oyama et al. reviewed the usage of a replication competent herpes simplex virus, G207. The G207 virus replicates in (and kills) cells that are rapidly dividing, such as tumor cells, but does not appear to replicate in normal cells. Although cytotoxic agent gene therapy approaches have demonstrated promising results for local tumor control, further studies are warranted to investigate systemic bystander and/or immune effects.