Thérapie génique anticancéreuse par gènes suicides : du gène à l'essai thérapeutique.

Abstract

Le premier système de gène suicide développé pour un usage de thérapie génique utilise la thymidine kinase du virus Herpes simplex de type 1 (HSV1-TK). Cette enzyme est capable de phosphoryler le ganciclovir, un analogue nucléosidique dont la forme triphosphate est fortement toxique pour les cellules en division. Dans ce système, la toxicité induite est conditionnelle, restreinte aux cellules en cycle et engendre un important effet de voisinage assurant la destruction de cellules tumorales non transduites. Cette approche a été largement validée par des études précliniques chez l’animal et fait maintenant l’objet de nombreux essais cliniques. Les premiers résultats ont révélé une excellente tolérance à la thérapie génique par gène suicide. Toutefois, l’efficacité du traitement reste aujourd’hui limitée par l’efficacité du transfert de gène. L’amélioration des vecteurs, l’optimisation des méthodologies de ciblage ainsi qu’une meilleure compréhension de l’effet de voisinage, et notamment sa composante immunologique, devraient maintenant permettre d’améliorer l’efficacité thérapeutique.

Suicide genes encode enzymes that are capable of converting a non toxic prodrug into toxic metabolites. The Herpes simplex type 1 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. In 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.