The proposed clinical trial for melanoma is based on the protocol developed and tested successfully in a mouse xenograft model of human melanoma. The trial protocol involves administering to melanoma patients an immunoconjugate composed of a human factor VII (fVII) molecule conjugated to the Fc region of a human IgG1 immunoglobulin. The immunoconjugate binds with high affinity and specificity to its natural receptor tissue factor (TF) expressed by tumor blood vessels and tumor cells. The fVII molecule is mutated to prevent initiation of blood coagulation after it binds to TF. The gene encoding the immunoconjugate is carried by a non-replicating adenoviral vector, which is injected directly into skin tumors of a melanoma patient. The adenovirus infects mainly the cells of the injected tumor, which synthesize the immunoconjugate for secretion into the blood, establishing a steady high blood titer of the immunoconjugate for several weeks. The blood-borne immunoconjugate binds to tumor blood vessels and tumor cells throughout a patient?s body, resulting in induction of a powerful cytolytic immune attack against primary and disseminated tumors. The mouse model experiments demonstrated that the immunoconjugate causes regression of human melanoma tumors, associated with extensive destruction of the tumor vasculature. No clinically significant adverse effects on normal tissues were detected in the treated mice. The safety and efficacy of the protocol in the mouse model suggest a similar outcome for the proposed clinical trial. Designed primarily as a dose escalation study of the safety of administering intratumoral injections of an adenoviral vector encoding the fVII immunoconjugate, the trial is also designed to generate efficacy data. Each melanoma patient enrolled in the trial will receive a selected dose of the vector administered at 3-day intervals for a total of 6 doses. Toxicity will be monitored by a panel of tests during and after treatment, including several types of blood and liver function tests. Efficacy will be monitored by measurements of injected skin tumors, and also of skin tumors and internal tumors that were not injected. Because the protocol should be applicable to a broad range of human solid tumors, a favorable outcome for the melanoma trial could lead to a new treatment not only for melanoma but also for other types of cancer.
| Tang, Y; Borgstrom, P; Maynard, J et al. (2007) Mapping of angiogenic markers for targeting of vectors to tumor vascular endothelial cells. Cancer Gene Ther 14:346-53 |
