GPI-ANCHORED MOLECULES AS THERAPEUTIC VACCINES

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DESCRIPTION (Adapted from the Applicant's Abstract): Tumors modified by transfecting genes for co-stimulatory molecules such as B7.1 are now being considered as a potential therapeutic tumor vaccine. However, transfection is not always efficient and can be difficult with many cell types, especially freshly isolated tumor cells from patients. The investigator proposes to determine efficacy of tumors modified with co-stimulatory molecules using a novel approach. Studies have shown that purified glycosyl phosphatidyl inositol (GPI)-anchored cell surface proteins can be spontaneously incorporated into cells by incubating the proteins with the cells. This unique property can be used to reconstitute cell surface expression receptors on cell membranes without the use of gene transfection. Using recombinant techniques, they have constructed and expressed the purified GPI-anchored B7.1 molecule on tumors. The investigator proposes to determine the immunotherapeutic potential of tumors reconstituted with GPI-B7 in inducing tumor specific immunity. Using in vitro human experiments and in vivo mouse experiments, optimal conditions for inducing tumor immunity will be determined. They will also determine whether cytokines can enhance the immunity induced by tumors modified with GPI-anchored molecules. Human tumor cell lines will be developed to determine the efficacy of GPI-B7.1 reconstitution on autologous tumor specific CTL development in vitro. Other co-stimulatory adhesion molecules such as GPI-ICAM-1 and heat-stable antigen will be developed and tested alone or in combination with B7.1, for the induction of tumor specific immunity. The results from the proposed research will demonstrate the efficacy and potential application of the GPI-anchored molecule modified tumors as a therapeutic vaccine for tumor immunotherapy. In the long term the knowledge obtained from this study could be used to develop an "artificial cell vaccine" to treat cancer.