Proof Of Concept Of A Gene Directed Enzyme Prodrug Therapy With An Intra-Arterial Delivery Of Mesenchymental Stem Cells In A Rabbit Vx2 Tumor Hepatic Model

Gene directed enzyme prodrug therapy (GDEPT) is a cancer gene therapy using a gene (optimized by mutations) encoding an enzyme delivered to tumor cells, and followed by administration of a pro-drug, which is converted locally into a cytotoxic by the mutated enzyme. The goal of our study is to assess feasibility and efficacy of a suicide gene therapy using transduced mesenchymal stem cells intra-arterially delivered into a VX2 liver rabbit tumor model. 11 rabbits with a VX2 liver tumor were randomly assigned into 3 groups. Control group A (1 rabbit) free of any treatment; Control group B (2 rabbits) received intravenous injection of 80mg/Kg cyclophosphamide at day 3 and 9; and Group C (8 rabbits) received the GDEPT treatment consisting in intra-arterial injection of transduced MSCs successively at day 0 and 11 followed by CPA injection at day 3 and 14. Animals were followed until sacrifice (day 25) by ultrasound scan and blood examination. All organ pathologic examination was performed after sacrifice. A significant tumor volume difference between control groups and group C was observed at D7 (p = 0.024); D11 (p = 0.024), and D25 (p = 0.048). Tumor necrosis was significantly greater for rabbits who received the GDEPT (78% of total tumor surface) compared with control animals (22% of total tumor surface (p = 0.006). Intra-arterial delivery of transduced MSCs with a suicide gene is feasible and caused significant tumor necrosis in a model of VX2 liver tumor.