lntratumoral injection of adenoviral vectors encoding tumor-targeted immunoconjugates for cancer immunotherapy

摘要

The efficacy and safety of a new immunotherapy protocol for cancer were tested in a severe combined immunodeficient mouse model of human skin and metastatic lung melanoma. The protocol involves intratumoral injections of replication-incompetent adeno- viral vectors encoding immunoconjugates composed of the Fc region of an lgG1 immunoglobulin conjugated to a tumor-target- ing domain. One targeting domain is factor Vll that binds to tissue factor expressed on endothelial cells lining the tumor neovascu- lature and on tumor cells; the active site of factor vll was mutated to inhibit the initiation of blood coagulation. Another targhting domain is a single-chain Fv antibody that binds to a cognate antigen expressed on human melanoma cells. The adenoviral vectors infect mainly the cells of the injected tumor, which syn- thesize and secrete the immunoconjugates. The bloodborne im- munoconjugates induce a cytolytic immune response against the targeted neovasculature endothelial cells and tumor cells. The mouse model experiments showed that intratumoral delivery of the factor Vll immunoconjugate, either alone or together with the single-chain Fv immunoconjugate, resulted in growth inhibition and regression of the injected tumor. and also of distant metastatic tumors, without evidence of damage to normal organs. There was extensive destruction of the tumor neovasculature. presumably mediated by the factor Vll immunoconjugate bound to tissue factor on neovasculature endothelial cells. Because tissue factor is gen- erally expressed on neovascular endothelial cells and tumor cells. a factor Vll immunoconjugate could be used for immunotherapy against a broad range of human solid tumors.