282621 Injectable Thermo-Sensitive Hydrogel As an Adjuvant: In Vivo Modulation of Dendritic Cells for Cancer Vaccine

Thursday, November 1, 2012: 8:48 AM
Pennsylvania East (Westin )
Kye-Il Joo, Liang Xiao, Yarong Liu and Pin Wang, Chemical Engineering and Materials Science, University of Southern California, Los Angeles, CA

Development of an effective vaccine for cancer involves eliciting a potent antitumor immune response by introduction of tumor antigens to trigger systemic immunity against the tumor. Dendritic Cells (DCs) are the most powerful antigen-presenting cells capable of initiating adaptive immune response by stimulating both T cells and B cells and therefore become one of the major target cells for the cancer vaccine development. 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. However, in vivo DC targeting approach is limited by low specificity and poor efficacy of antigen uptake to DCs. Thus, the ability to efficiently deliver antigens to host DCs in vivo is a crucial step towards generating a potent antitumor immunity.

In this study, we hypothesized that creating in vivo microenvironment to recruit and proliferate DCs, which mimics natural surroundings of infection in the body, may potentially provide a practical mean to enhance the uptake of antigens to host DCs and precisely control the timing of DC-trafficking and activation in situ. Therefore, we investigated the development of the functionalized biomaterials incorporating inflammatory cytokines as infection-mimicking microenvironment for recruiting and housing host DCs in vivo prior to introduce tumor antigens at the DC-enriched site. This approach involves the design and use of thermo-sensitive mPEG-PLGA hydrogel capable of solution-gel transition in the response to temperature, which facilitates drug loading and exhibits sustained release of the drug. The implantation of the hydrogel loaded with granulocyte-macrophage colony-stimulating factor (GM-CSF), which has been identified as a potent stimulator of DC recruitment and proliferation, could provide the subcutaneous microenvironment where host DCs could be recruited and proliferated by the sustained and localized release of GM-CSF at the hydrogel-injected site. Analysis of in vivo DC recruitment showed that the number of recruited DCs was peaked at around 7 to 10 days post-injection of GM-CSF hydrogel. The migration assay indicated that the recruited DCs were able to migrate to lymph node where T-cell response was triggered. Furthermore, our lymphocyte analysis suggested that the significantly improved antigen-specific immune responses were observed when immunogens (i.e. antigens) were administrated at the site of GM-CSF-hydrogel implanted at 7 days post-injection, compared to empty hydrogel or without hydrogel. In this presentation, this hydrogel adjuvant system with many different immunogens including lentiviral vector and liposome/protein will be discussed in more detail.

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