Targeting tumor vasculature endothelial cells and tumor cells for immunotherapy of human melanoma in a mouse xenograft model

An immunotherapy treatment for cancer that targets both the tumor vasculatu re and tumor cells has shown promising results in a severe combined immunod eficient mouse xenograft model of human melanoma. The treatment involves sy stemic delivery of an immunoconjugate molecule composed of a tumor-targetin g domain conjugated to the Fc effector domain of human IgG1. The effector d omain induces a cytolytic immune response against the targeted cells by nat ural killer cells and complement. Two types of targeting domains were used. One targeting domain is a human single-chain Fv molecule that binds to a c hondroitin sulfate proteoglycan expressed on the surface of most human mela noma cells. Another targeting domain is factor VII (fVII), a zymogen that b inds with high specificity and affinity to the transmembrane receptor tissu e factor (TF) to initiate the blood coagulation cascade. TF is expressed by endothelial cells lining the tumor vasculature but not the normal vasculat ure, and also by many types of tumor cells including melanoma. Because the binding of a fVII immunoconjugate to TF might cause disseminated intravascu lar coagulation, the active site of fVII was mutated to inhibit coagulation without affecting the affinity for TF. The immunoconjugates were encoded a s secreted molecules in a replication-defective adenovirus vector, which wa s injected into the tail vein of severe combined immunodeficient mice. The results demonstrate that a mutated fVII immunoconjugate, administered separ ately or together with a single-chain Fv immunoconjugate that binds to the tumor cells, can inhibit the growth or cause regression of an established h uman tumor xenograft, This procedure could be effective in treating a broad spectrum of human solid tumors that express TF on vascular endothelial cel ls and tumor cells.