| The complexities of tumor immunology suggest that innovative measures will be necessary to develop a vaccine for cancer. Increasingly, dendritic cells (DC) are emerging as a "central switchboard" of the immune system and thus represent an ideal junction from which to initiate anti-tumoral immunity. The most challenging obstacle has been the means by which to convey tumor Ag encoding genes to DC. Low efficiency gene transfer has encumbered conventional gene delivery approaches, and adenoviral (Ad) vectors are no exception. Reasoning this poor gene transfer as a potential defect in Ad entry, we have established a deficiency of the primary Ad binding receptor, Coxsackie adenovirus; receptor (CAR), on human monocyte-derived DC (MDDC).;By means of bispecific Abs, we have circumvented the deficiency of CAR by redirecting Ad binding to an alternate receptor expressed on DC. The results have shown that by targeting Ad vectors to the cellular receptor CD40, gene transfer to DC could be increased considerably. More importantly, DC infected by this targeted vector underwent a "maturation" that enhanced their capacity to present Ags to other immune cells. These findings are commensurate with the established role of CD40 activation in native activation of DC.;To evaluate the in vivo utility of these genetically modified DC, we have coupled this retargeting approach with Ad vectors carrying genes for a defined tumor Ag. Human papillomavirus (HPV) is the causative agent of human cervical cancer, and thus, because expression of the HPV E7 gene is restricted to tumor cells, E7 Ag represents an ideal vaccine candidate. In an animal model of tumors induced by HPV, we have established prophylactic immunity against tumor challenge. Further, this strategy can initiate therapeutic immunity against established tumors that extends survival of tumor bearing animals. Finally, we have established that CTLs are a major effector cell in this antitumoral immune response. These findings suggest that gene-based vaccination of DC with tumor. Ags can instigate productive antitumoral immunity and may have implications for the treatment of human cancer. |
