Suicide gene-based anti-cancer gene therapy: from the gene to clinical trials

Suicide genes encode enzymes that are capable of converting a non toxic prodrug into toxic metabolites. The Herpes simplex type I thymidine kinase and the prodrug ganciclovir which it phosphorylates define the prototypic suicide gene system endowed with interesting properties for a clinical use, notably for cancer treatment. Toxicity is due to DNA elongation impairment by triphosphorylated ganciclovir, providing specificity for dividing cells; there exists a major bystander effect by which untransduced dividing cells are killed together with transduced dividing cells during ganciclovir treatment, providing efficacy; the toxicity is doubly conditional, depending on both transgene expression and ganciclovir administration, providing safety. This system has been successfully used for treating many experimental tumors transduced by either retroviral or adenoviral vectors. These experiments have revealed that there also exists in vivo an important bystander effect which acts not only intratumorally, but also at a distance. Tumors in which less than 10 % of the cells have been transduced with HSV1-TK are often eradicated by ganciclovir treatment. Ln addition, tumors located at a distance with no contact with these treated tumors are also dramatically affected. This bystander effect is a key element for treatment efficacy, and is in large part immune-mediated. Indeed, treated and untreated tumor are infiltrated by cells of the immune system, and the bystander effect is much reduced in immuno-compromised animals. Many clinical trials have been undertaken using this system. From the published data, it appears that the treatment is most often very well tolerated. In addition,there are preliminary indications for a potential efficacy that will have to be confirmed in larger trials including control groups. Altogether, these results warrant the development of this therapeutic strategy for the treatment of cancer. There are numerous possibilities for ameliorating treatment efficacy, notably through the improvement of gene transfer and a better understanding of the molecular mechanisms of the bystander effect. We thus believe that suicide gene therapy may become an efficient anticancer treatment in coming years.