The focus of this project is on the potential of developing a new treatment modality for metastatic colon carcinoma by somatic gene therapy, using a combination of suicide and cytokine genes. The project is based on the following hypotheses (1) tumor cells killed in vivo by the suicide gene will undergo phagocytosis by antigen presenting cells which process and present the tumor antigen(s) to the T cells; (2) this process, as well as subsequent T-cell responses, will be enhanced in the presence of local cytokine expression; (3) long-term anti-tumoral T-cell responses can be established in the combination treated animals. In particular the investigator will examine the role of GM-CSF in the in vivo antigen presentation, and the proposed connection between proper antigen presentation. local cytokine expression, and long term immunity by in vitro antigen presentation assay and primed APC adoptive transfer experiments. Also, he will determine whether the combination gene therapy can establish tumor specific memory cytotoxic T cells by the frequency analysis of memory cytotoxic T cell precursors and whether these memory T cells can be clonally expanded into effector cytotoxic T cells and confer protective immunity in syngeneic irradiated naive animals by memory T cell adoptive transfer. He believes that the scientific information generated by axis study can be utilized to further improve the development in combination gene therapy against metastatic colon carcinoma in vivo.
