Complement is a crucial component of the immune system that can be involved in an effector response to tumor cells, and can also enhance the induction phase of a humoral immune response. Nevertheless, immunotherapy using complement activating antibodies that are specific for tumor-associated antigens has met with only limited success. A significant factor in the resistance of tumor cells to antibody-mediated immunotherapy is the expression of complement inhibitory proteins that are often upregulated on the tumor cell surface. It is hypothesized that the downregulation of complement inhibitors expressed on tumor cells will significantly enhance tumor sensitivity to antibody-mediated immunotherapy and may also enhance the outcome of a normally ineffective humoral immune response. Although frequently upregulated on tumor cells, complement inhibitory proteins remain largely unexplored as targets for cancer therapy due to their widespread expression. For some cancers, intracavitary delivery of a therapeutic reagent to modulate complement inhibitor function may obviate a requirement for specialized targeting strategies. It is proposed to investigate a therapeutic strategy involving intravesical (bladder) delivery of small interfering RNAs (siRNAs) to downregulate complement inhibitory proteins on bladder tumor cells, together with intravenous administration of a complement activating mAb directed against a bladder cancer-associated antigen. Optimum siRNA sequences for downregulation of complement inhibitory proteins on a mouse bladder cancer cell line will be determined in vitro. Selected siRNA sequences will be used to determine optimum strategy for siRNA/gene delivery to tumor cells in an orthotopic syngeneic mouse model of bladder cancer. Naked siRNAs and adenoviral vector delivery of siRNA will be investigated. Finally, the effect of complement inhibitor downregulation on the immune response to bladder cancer in the absence and presence of intravenously administered mAb immunotherapy will be investigated in an orthotopic mouse model.
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