Systemic administration of a matrix-targeted retroviral vector is efficacious for cancer gene therapy in mice

Targeting cytocidal vectors to tumors and associated vasculature in vivo is a long-standing goal of human gene therapy. In the present study, we demon strated that intravenous infusion of a matrix (i.e., collagen)-targeted ret roviral vector provided efficacious gene delivery of a cytocidal mutant cyc lin G1 construct (designated Mx-dnG1) in human cancer xenografts in nude mi ce. A nontargeted CAE-dnG1 vector (p = 0.014), a control matrix-targeted ve ctor bearing a marker gene (Mx-nBg; p = 0.004), and PBS served as controls (p = 0.001). Enhanced vector penetration and transduction of tumor nodules (35.7 +/- 1.4%, mean +/- SD) correlated with therapeutic efficacy without a ssociated toxicity, Kaplan-Meier survival studies were conducted in mice tr eated with PBS placebo, the nontargeted CAE-dnG1 vector, and the matrix-tar geted Mx-dnG1 vector. Using the Tarone log-rank test, the overall p value f or comparing all three groups simultaneously was 0.003, with a trend that w as significant to a level of 0.001, indicating that the probability of long -term control of tumor growth was significantly greater with the matrix-tar geted Mx-dnG1 vector than with the nontargeted CAE-dnG1 vector or PBS place bo. The present study demonstrates that a matrix-targeted retroviral vector deployed by peripheral vein injection (1) accumulated in angiogenic tumor vasculature within 1 hr, (2) transduced tumor cells with high-level efficie ncy, and (3) enhanced therapeutic gene delivery and long-term efficacy with out eliciting appreciable toxicity.