Although many agents induce apoptosis, they are commonly associated with side effects that compromise health. TRAIL (TNF-related apoptosis-inducing ligand)/Apo-2L is generating excitement because it induces apoptosis in a wide range of tumor cells but not in normal cells and tissues. Preclinical studies using systemic TRAIL/Apo-2L doses are safe and can suppress tumor growth in vivo. Large amounts of TRAIL/Apo-2L are, however, needed to inhibit tumor formation, primarily because of the short in vivo half-life of the protein. Therefore, an alternative means of delivery may increase the relative activity of TRAIL/Apo-2L such that larger, more established tumors can be eradicated as efficiently as smaller tumors. This year in the U.S. approximately 30,000 new cases of renal cell carcinoma (RCC) will be diagnosed and nearly 12,000 deaths are expected from RCC. Metastatic RCC carries a median survival of 8 months and almost 30% of RCC patients are diagnosed with advanced metastatic disease. Furthermore, RCC is highly resistant to chemotherapy, a possible consequence of its association with the multidrug-resistance P-glycoprotein. RCC is regarded as an immunogenic tumor, with many reports of spontaneous regression and evidence of tumor-specific immune responses being a strong indicator of the immunogenicity of RCC. Thus, immunotherapy is being intensely studied as a treatment for RCC. Unfortunately, the response rates have been poor and significant toxicity reported, limiting the use of immunotherapy in the treatment of RCC. Gene transfer therapy offers new alternatives in the treatment of RCC. Employment of non-replicative viral gene delivery systems is making it possible to administer genes directly into tumors in situ. Previously, we described the cytotoxic activity of recombinant TRAIL/Apo-2L protein against human RCC cell lines, and the development and testing of a recombinant, replication-deficient adenoviral vector encoding the human TRAIL gene (Ad5-TRAIL). Transfer of the TRAIL gene into human tumor cells in vitro and in vivo, using immunodeficient mice, led to the rapid production and expression of TRAIL/Apo-2L protein, and apoptotic death of the tumor cells. However, it remains unknown whether Ad5-TRAIL will inhibit tumor growth in immunocompetent animals, and if the Ad5-TRAIL-induced tumor cell death will activate systemic antitumor immunity. With this in mind, the proposed project will employ a novel adenoviral vector encoding the mouse TRAIL gene (Ad5-mTRAIL) combined with agents to boost systemic immune responses through augmenting antigen presentation and stimulating T cell expansion to develop unique approaches for the treatment of RCC.
Specific Aims : (1) Investigate the ability of DC to present antigens derived from apoptotic Renca cells to stimulate antitumor immunity and analyze the effector cells and mechanism of tumor rejection; and (2) Examine the ability of Gelfoam R and depsipeptide (FR901228) to augment Ad5-mTRAIL infectivity and transgene expression, making Ad5-mTRAIL gene transfer therapy more potent.
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