GENE-THERAPY WITH RECOMBINANT ADENOVIRUS VECTORS - EVALUATION OF THE HOST IMMUNE-RESPONSE

E1, E3-deleted, replication-deficient recombinant adenoviruses are wid ely studied as vectors for their capacity to transfer therapeutic gene s in vivo. They can infect a wide variety of dividing and quiescent ce lls from different organs and possess a large packaging capacity. One of the major limitations in the use of these vectors for gene therapy is the transient expression of the transgene in vivo and the poor tran sduction efficiency when re-administered. Despite the deletion of the viral El region, low level of early and late viral genes are expressed in vivo. Thus, viral antigens plus those derived from transgene expre ssion in transduced cells contribute to cellular immune responses lead ing to the destruction of these cells. Production of anti-adenovirus a ntibodies, the cellular immune response as well as the early non-speci fic clearance of the vectors, constitute barriers to successful gene t herapy. New vectors have been derived with additional deletions in the E2a or the E4 regions. Such second generation vectors were evaluated in vivo. These studies have revealed the complexity of the immune mech anisms elicited by these vectors and the importance of several paramet ers in these evaluations (i.e. mouse strains, nature of the transgene, route of administration...). In order to inhibit the production of ne utralizing antibodies to adenovirus that prevent from further readmini stration of the vectors, immunosuppressive strategies were undertaken. Treatment regimens with immunosuppressive drugs (cyclophosphamide, FK 506) or with monoclonal antibodies that block either the T cell recept or or costimulation pathways allow prolonged transgene expression and/ or readministration of adenoviral vectors. In addition, transduction e fficiencies may be increased by transiently inhibiting non-specific im mune mechanisms that lead to the dramatic early clearance of the vecto rs. Taken together, these strategies may improve further gene therapy protocols by decreasing the host immune response to adenoviral vectors . (C) 1997 Elsevier Science B.V.