EXTENDED-RELEASE OF ADENOVIRUS FROM POLYMER MICROSPHERES - POTENTIAL USE IN GENE-THERAPY FOR BRAIN-TUMORS

Current protocols for the treatment of intracerebral glioma are inadeq uate, with limited reduction in morbidity or mortality. As such gene t herapy paradigms have been developed. Initial progress in rodent model s using in situ introduction of retroviral vector producer cells to tr ansfer a cytotoxic gene product led to phase I clinical trials with li mited success, due in part to immune responses to murine producer cell s along with low level gene transfer. We and others have initiated stu dies to determine the effectiveness of adenoviral vectors to deliver c ytotoxic and/or immune-stimulatory gene products directly to tumor. Ad enoviral vectors can be purified to high titers, are relatively stable upon formulation and storage, and can infect both dividing and non-di viding tumor cells. Also, they can be introduced in situ without helpe r virus or producer cells. However, gene transfer to glioma tissue wit h recombinant adenoviruses is not efficient, with multiplicities of in fection greater than 50 infectious units/cell required for efficacy. A t these doses the virus induces a potent immune response that further reduces gene transfer following re-administration. The inflammatory re sponse to low doses of recombinant adenoviral vectors is less robust a nd does not preclude re-administration. Thus, strategies to increase e fficiency coupled to low dose administration are desirable. To accompl ish low dose administration we have developed a method to formulate re combinant adenoviral vectors in biodegradable microspheres. Poly (lact ic-glycolic) acid (PLGA) microspheres containing recombinant adenoviru s were prepared using a double emulsion technique, and viable virus re leased for greater than 10 days. (C) 1997 Elsevier Science B.V.