(142f) Injectable Thermosensitive Hydrogels Containing Cytokines for Modulating Dendritic Cell-Derived Immune Responses

Development of an effective vaccine and immunotherapy technology for cancer involves eliciting a potent tumor antigen-specific immune response by introduction of tumor antigens and generating systemic immunity against the tumors. Dendritic cells (DCs) are the most powerful antigen-presenting cells, capable of initiating immune response by stimulating both T cells and B cells, and much effort has therefore been devoted to methods for delivering appropriate antigens to DCs to develop effective vaccines. Immunization by adoptive transfer of autologous DCs that are loaded with antigens in vitro is, however, labor-intensive and requires significant regulatory concerns. In addition, most transplanted DCs remain non-functional, and few home to the lymph nodes where the subsequent activation of T-cell immunity is induced. More cost-effective and efficient protocols involve delivering antigen to host DCs in vivo by direct injection of vaccine vectors to program DCs in situ. Thus, the ability to deliver antigens to host DCs in vivo is a key step towards generating a potent antitumor immunity. 

In this study, we demonstrate a general strategy to enhance antigen-uptake by DCs in vivo. It depends on recruiting and housing host DCs at the immunization injection site using functionalized biomaterials incorporating inflammatory cytokines. This approach offers the sustained and localized release of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), which has been identified as a potent stimulator of DC recruitment and proliferation, from the subcutaneously injected hydrogels. The hydrogel materials provide a controllable subcutaneous microenvironment where host DCs could be recruited and further educated in situ by following injection of immunogens (antigens) at the recruited site. Thermo-sensitive mPEG-PLGA hydrogels capable of solution-gel transition through changes in temperature enable greater efficiency of drug/cytokine loading and also exhibit a sustained and localized release of GM-CSF in the target site. The enhanced antigen-specific immune response was observed when viral vector-based vaccine carriers were administered at the site implanted with these engineered hydrogel biomaterials.