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Förslaget inkom 2002-10-14

Use of filamentous phage to target host immune system against renal cell cancer (RCC)

Background: Despite extensive evaluation of many therapeutical strategies, metastatic RCC remains highly resistant to conventional treatment modalities and the 5-yr survival rate for patients with stage IV disease is below 10%. IFN-a, IL-2, or both demonstrate low response rate 10-20 %. Response can be dramatic but is rarely durable. Because most patients do not achieve response, these agents are not considered effective treatments for RCC. Preliminary reports suggest that tumor-specific phages might direct the immune response against the tumor.

Research plan: As a proof-of-principle the specificity of the binding of whole phages to tumors in vivo, will be tested using a model hepatitis C virus (HCV) antigen. These experiments should provide information 1) if reduction in tumor mass really occurs; 2) if it is a specific or non-specific phenomenon; 3) about the type of immunocompetent cells involved in the process. As a second step anti-RCC-specific phages will be generated in order to demonstrate the efficacy of this approach in a model setting with RAG and RENCA RCC cell lines.

Preliminary results: Phages specific for a well-characterized antigen of HCV (model antigen) were generated, as well as a stable transfected B16 tumor cell line. A RCC cell lines RENCA and RAG are available at our laboratory at CCK. The study has been approved by the Ethics committe (Dnr.N143/00).

Practical methods: Tissue culture, transfection of genes in vitro, PCR, plasmid purification, immunohistochemistry, phage display, flow cytometry.

Significance: The proposed preclinical study if successful will have a major impact on the treatment of RCC. It will enable tumor debulking in metastatic disease prior to other immunotherapeutical approaches, which are also under development in our laboratory.

This project is in close collaboration with Mats AA Persson, Center for Molecular Medicine, KI


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