1013. Pharmacology of Tropism Modified Adenovectors for Therapy of Disseminated Cancer

Abstract

Generation of tropism modified adenovirus vectors with improved pharmacokinetics and bioavailability is likely to be critical for their application to the treatment of disseminated cancer. The goal of our studies is to identify strategies that enhance anticancer activity as well as reduce impact on normal tissues. Modification of the receptor binding tropism has been accomplished and results in preferential transduction of target cells. We have created vectors that are ablated for binding to native CAR and integrin receptors. Additionally, a binding ligand or a tumor-selective peptide motif can be inserted into the HI loop of fiber. We have evaluated the pharmacokinetics and biodistribution and of the tropism modified vectors in mice following intra-peritoneal administration. At a low dose, such as 1 |[times]| 1010 particle units (pu), selective tumor transduction in the peritoneal cavity was demonstrated by a vector that contains RGD-4C peptide ligand. At a low dose targeted and untargeted vectors are apparently retained in the peritoneal space. Wild type vectors showed transduction mediated by CAR interaction mainly observed in the abdominal organs and tissues. Mesothelial transduction was significantly reduced by the ablation of CAR binding. At a high dose, such as 3 |[times]| 1011 pu, a considerable proportion of viral particles were transported from the peritoneal space to the bloodstream. Sustained levels of active particles could be measured in the circulation using the vectors ablated for CAR binding. Initial studies indicate that determinants outside the fiber knob and penton base control trafficking of vector out of the peritoneal space. Sustained systemic vector circulation is essential to achieve selective transduction of disseminated subcutaneous tumors that expressed either a pseudo-receptor or beta 6 integrin as a targeted receptor. We are currently testing tropism modified vectors containing the therapeutic transgene, TNF under the direction of constitutive and tissue selective promoters. Such vectors show promising targeting and anti-tumor activity in preclinical models of human cancer.