Sustained release of granulocyte-macrophage colony-stimulating factor froma modular peptide-based cancer vaccine alters vaccine microenvironment andenhances the antigen-specific T-cell response

The recent identification and molecular characterization of tumor antigens provides the opportunity to explore the rational development of peptide-bas ed cancer vaccines, However. the response to these vaccines remains variabl e, and peptide-based cancer vaccines may even produce tolerance induction a nd enhanced tumor growth. The authors have developed a unique method for th e isolation of a polysaccharide polymer of chemically pure poly-N-acetyl gl ucosamine (p-GIcNAc). This highly purified polysaccharide can be formulated into a stable gel matrix (designated F2 gel matrix) with unique properties of a sustained-re lease delivery system that has previously been shown to be an effective immune adjuvant. F2 gel matrix is capable of providing sust ained release of antigenic peptide and cytokine in vitro. The purposes of t his study were to characterize the ability of F2 gel matrix to provide sust ained local release of cytokines in vivo and to test the hypothesis that su ch sustained release can enhance th microenvironment for antigen presentati on, leading to a more effective antitumor response. Subcutaneous administra tion of F2 gel/cytokine matrix resulted in sustained release of cytokine at the vaccine site for up to 120 hours. Sustained release of granulocyte-mac rophage colony-stimulating factor (GM-CSF) was associated with an increased inflammatory infiltrate at the vaccine site and enhanced dendritic cell ac tivation. Further, accination with F2 gel/SIINFEKL/GM-CSF matrix resulted i n enhanced antigen-specific immunity. Addition of GM-CSF to the F2 gel matr ix resulted in an increase in the percentage of antigen-specific T cells in the draining lymph nodes, enhanced cytotoxicity, a sustained presence of a ntigen-specific T cells in the peripheral blood, and protection from E.G7 t umor challenge. These results support the potential of an F2 gel matrix mod ular vaccine delivery system that can provide sustained local release of cy tokine in vivo, and confirm the powerful effects of GM-CSF as an immune adj uvant.