To develop a method to overcome the anergy that exists in
tumor hosts to
cancer, we have designed an adenoviral vector for the in vivo activation and
tumor antigen loading of dendritic cells. This adenoviral vector encodes a fusion
protein composed of an amino-terminal
tumor-associated
antigen fragment fused to the
CD40 ligand (
CD40L).
Subcutaneous injection of an adenoviral vector encoding a fusion
protein of the human papillomavirus E7 foreign
antigen linked to the
CD40L generates CD8+ T cell-dependent immunoresistance to the growth of the E7-positive syngeneic TC-1
cancer cells in C57BL/6 mice for up to 1 year. We also studied the s.c. injection of a vector carrying the gene for the human MUC-1 (hMUC-1)
self-antigen fused to the
CD40L. When this vector was injected into hMUC-1.Tg mice, which are transgenic for the hMUC-1
antigen, the growth of syngeneic hMUC-1-positive LL1/LL2hMUC-1 mouse
cancer cells was suppressed in 100% of the injected animals. The hMUC-1.Tg mice are anergic to the hMUC-1
antigen before the injection of the vector. These experimental results show that it is possible to use vector injection to activate a long-lasting cellular immune response against
self-antigens in anergic animals. The vector-mediated in vivo activation, and
tumor-associated
antigen loading of dendritic cells does not require additional
cytokine boosting to induce the immune response against the
tumor cells. This vector strategy may therefore be of use in the development of
immunotherapy for the many
carcinomas in which the hMUC-1
antigen is overexpressed.