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Adenoviral Vectors Targeted to CD40 Enhance the Efficacy of Dendritic Cell-based Vaccination against Human Papillomavirus 16-induced Tumor Cells in a Murine Model¹

Division of Human Gene Therapy, Departments of Medicine, Pathology, and Surgery, and Gene Therapy Center, University of Alabama at Birmingham, Birmingham, Alabama 35294 [B. W. T., T. L. H., J. T. D., D. T. C.], and Department of Medical Oncology, Academic Hospital of the Free University, Amsterdam, 1081 BT, the Netherlands [T. D. D.]

Dendritic cells (DCs) represent a unique junction from which to initiate antigen-specific immunity. One of the most challenging obstacles for DC-based immunotherapy has been the means by which to convey tumor antigen-encoding genes to DCs. In this study, we show that adenoviral (or adenovirus, Ad) vectors targeted to CD40 by means of bispecific antibodies can enhance gene transfer to murine DCs. Moreover, we illustrate that this vector initiates phenotypic changes characteristic of DC maturation. To explore the in vivo potential of this strategy, we coupled this targeting approach with an Ad vector carrying the gene for a tumor antigen. In particular, the human papillomavirus (HPV) E7 antigen represents an attractive target for antigen-specific immunity of cervical cancer. Relative to DCs infected by untargeted Ad, DCs infected by AdE7 targeted to the receptor CD40 enhanced protection against HPV-16-induced tumor cells in a murine model. We have further established that this protection was both antigen specific and CD8+ T-cell dependent. Illustrating that Ad-modified DCs may be used in repeated vaccination, we report that preimmunization of animals with Ad infected DCs prior to E7 vaccination only moderately reduced vaccine efficacy. Finally, we have observed that CD40-targeted AdE7 can initiate partial therapeutic immunity in mice bearing established tumors. These findings suggest that gene-based vaccination of DCs with tumor antigens can elicit productive antitumoral immunity and that enhancements in gene transfer efficacy and/or DC maturation may facilitate this process.

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