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At The University of Texas M.D. Anderson Cancer Center, we have been investigating use of the adenovirus type 5 ElA gene as a cancer therapy for breast or ovarian cancer since 1995. ElA gene therapy is a nonimmunologic approach involving ectopic expression of a potentially therapeutic gene in cancer cells. During the late 1980s, E1A was shown to downregulate the overexpression of HER-2/neu, thus reversing the tumorigenic and metastatic phenotype of HER-2/neu-overexpressing breast and ovarian cancer cells. Since that time, E1A has also been shown to function as a tumor suppressor gene in several other types of tumor cells by inducing apoptosis and differentiation and by inhibiting metastasis regardless of HER2 expression level. This chapter highlights some of the issues and difficulties we encountered in designing clinical trials of E1A gene therapy for breast or ovarian cancer.

PV701 is a highly purified, replication-competent naturally attenuated strain of Newcastle disease virus, an avian paramyxovirus. PV701 directly lyses diverse human cancer cells in vitro (oncolytic) while being significantly less toxic toward normal human cells. In addition to its direct oncolytic properties, PV701 is capable of stimulating T-cell-mediated specific antitumor immunity and nonspecific activation of immune function, including interferon release and activation of tumoricidal macrophages. A high rate of complete tumor regression is observed in athymic mice implanted with human tumor cells following PV701 administered intravenously, or by intraperitonel or intratumoral routes. Objective responses have been observed in human phase I clinical trials of diverse tumor types. PV701 thus warrants further study as a novel therapeutic agent for cancer patients.

The protein encoded by the melanoma differentiation-association gene 7 (MDA-7/IL-24) is a novel interleukin (IL)-10 family cytokine with unique tumor-specific apoptotic and antiangiogenic properties that make it especially attractive for use in cancer gene therapy applications. Mda-7 gene transfer with a replication incompetent adenoviral vector (Ad-mda7) induces apoptosis in a tumor specific manner, an effect that is independent of the status of other tumor suppressor genes, such as p53, Rb, or pl6^INK4. In addition to its direct cytotoxic effects, Ad-mda7 transduction causes secretion of a processed, glycosylated form of MDA-7 protein. MDA-7 is a novel interleukin (IL-24) with unique apoptotic functions. Studies on the secreted MDA-7/IL-24 protein have shown that it can act as a pro-Thl cytokine, and induces secretion of interferon-gamma, tumor necrosis factor-α, IL-6, IL-12, and granulocyte macrophage colony-stimulating factor in human peripheral blood mononuclear cells. Additional studies in syngeneic mice indicate that MDA-7 can function as an immune adjuvant and enhance immune reactivity against tumors. More recently, our group demonstrated that MDA-7 protein functions as a potent antiangiogenic factor in vitro and in vivo that is 50-fold more active than angiostatin or endostatin. In phase I clinical trials intratumoral delivery of Ad-mda7 showed tumor regression in patients with advanced carcinomas who failed conventional therapies. This chapter provides a comprehensive perspective on MDA-7/IL-24 research, highlighting its proapoptotic, antimetastatic, and antiangiogenic properties. The combination of these potent effector mechanisms makes mda-7/IL-24 a promising and novel approach for the treatment of cancer.

This chapter describes preclinical development of therapeutic genes in breast cancer treatment. Beginning from targeting HER-2/neu-overexpressing breast cancer cells by adenovirus E1A, we found E1A expression had profound effects on tumor cells including growth suppression, apoptosis, and sensitization to chemo-drugs and radiation. The mechanisms of the antitumor activities as well as the preliminary results obtained from multiple E1A clinical trials are discussed. Also identified are the antitumor activity of interferon inducible genes, p202 and IFIX , and a proapoptotic gene, bik . The mechanism of action and the therapeutic potential of these genes in breast cancer models are also discussed.

This chapter reviews the requisite steps in a translational cancer gene therapy trial. As with all clinical trials, translational cancer gene therapy trials require clear concise objectives and endpoints. Several unique factors exist with gene therapy trials that must be considered prior to trial development, including the type of vector desired, the delivery mechanism and the different gene therapy strategies required for gene product expression. Progression of cancer gene therapy trials from the preclinical phase to the post approval phase IV stage require a careful strategy to meet the strict regulatory requirements at both the federal and local institutional level. Safety monitoring is especially important with gene therapy trials because of the high visibility of gene therapy trials and the impact on the trial, patient, and the gene therapy field in general if adverse events occur. Financial considerations should be addressed at the outset because of the increased costs associated with a translational gene therapy trial.