Cancer Gene Therapy Approaches at Aventis/Gencell

Abstract

Aventis/Gencell has been committed to the development of Gene Therapy since 1994. We have (1) an active ongoing clinical phase 11/111 program on using Adeno-p53 direct injection to solid tumors. AD5CMV-p53 has been evaluated as a monotherapy. Numerous reports in the literature support and extend that introduction of wild-type p53 gene in p53-deficient cells/tumors increases sensitivity to either chemo or radiotherapy. Chemo/radiotherapy sensitization using wtp53 can be very powerful for all the chemo/radiation-resistant tumors. (11). The immunotherapy project involves using the prodrug/ suicide gene (GCV/TK) and immunoindulators GM-CSF and IL-2. Pre-clinical data showed that direct injection of Adenoviral vectors containing the three genes to the local tumors, will have antitumor effect, inhibition of distant mets, prolonged life span, increased lymphocytes infiltrates, both the TH and TC cells, and tumor specific cytotoxicity. Taking advantage of the enhanced immunostimulatory, inflammatory microenvironment in the local tumor, the hope is to have enhanced systemic immune reaction to eliminate distant metastasis. (111). For antiangiogenic gene therapy, we are using inhibitors of endothelial cell proliferation and cellular invasions. For example, binding of urokinase type plasmonogen activator (uPA) to its receptor uPAR starts cascades leading to extracellular matrix degradation and endothelial cell proliferation. ATF acts as an antagonist of the uPA binding to its cell surface receptor. AdmATF inhibited primary tumor growth by targeting angiogenesis and interfered with tumor cell establishment at the distant sites in animal studies. From these results, using angiogenic inhibitors in cancer treatment presents a promising anti-cancer gene therapy approach. The great challenges ahead of us are how to design effective and combinational therapies, how to deliver the genes to the specific cells or tissues, and how to control the gene expression and regulation. We are also interested in developing in vivo gene delivery viral and non-viral systems to target to specific tumors and tumor vasculature.