Cytokines play a central role in the induction and regulation of immune response. Physiologically, they act in a paracrine rather than endocrine fashion. Experiments with cytokine gene transduced tumor vaccines have demonstrated that the paracrine release of certain cytokines at the site of the tumor results in priming of immune responses against certain tumor antigens. A broad comparative analysis of multiple cytokine genes demonstrated that GM-CSF transduced tumor vaccines produced a particularly potent systemic immune response. Paracrine GM-CSF vaccines enhance the presentation of tumor-specific antigens to the immune system and induce expression of co-stimulatory signals for T cell activation. A major limitation in the translation of this strategy to clinical practice is the labor intensity and technical difficulty of reliably generating genetically-altered tumor vaccines for the majority of patients. Recently, Dr. Pardoll and Leong's laboratories have developed an alternative to gene transfer by providing the local and sustained delivery of cytokines through biodegradable polymer microspheres. The hypothesis was that synthetic controlled release microspheres containing cytokines, mixed with irradiated autologous tumor cells, can replace the requirement for gene transfer and in vitro tumor expansion, while maintaining the ability to generate an effective, systemic antitumor immune response. This project proposes to apply this polymer based paracrine cytokine adjuvant approach to E7 and HER-2/neu specific vaccines by incorporating recombinant protein and/or peptides into timed release biodegradable polymer microspheres mixed with GM-CSF containing polymer microspheres. Specifically, we plan to: 1. Optimize functional GM-CSF-containing microspheres. 2. Produce recombinant E7 and HER-2/neu protein and peptides and incorporate them into polymer microspheres. 3. Optimize E7 and HER-2/neu vaccines by testing different combinations and formulations of microspheres containing recombinant protein and/or peptide mixed with GM-CSF containing microspheres. 4. Characterize the types of E7 and HER-2/neu specific cellular (helper and cytotoxic) and humoral immune responses elected by these polymer microsphere based vaccines. 5. Evaluate potential synergies between these polymer microsphere based vaccines and other vaccine approaches being developed in this NCDDG.
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