Access Type

Dissertation/Thesis

Date of Award

January 2019

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemical Engineering and Materials Science

First Advisor

Haipeng Liu

Abstract

Immunotherapy is emerging as one of the most promising therapeutic strategies for cancer treatment in clinical practice. Immunotherapy leverages the host’s immune system to attack and kill tumor cells. Rationally-designed cancer vaccines are emerging as one of the powerful immunotherapies primarily because of the promise of inducing tumor antigen-specific immune responses. To improve immunogenicity of cancer vaccines, vaccine antigens are administered with vaccine adjuvants which can robustly activate innate immune system and subsequently lead to adaptive immune response. However, the major challenge of achieving significant therapeutic efficacy is lack of efficient targeted-delivery of vaccine components. By taking advantage of endogenous albumin, lipid modified oligonucleotides-based adjuvants can be efficiently transported to draining lymph nodes (dLNs), where a variety of immune cells reside, and subsequently activate the adaptive immune system. This “albumin-hitchhiking” strategy represented a novel and efficient way for LN-targeted delivery of biologics, improving the therapeutic efficacy in cancer vaccines.

The aims of this dissertation are to further expand the scope of “albumin-hitchhiking” approach in immunomodulation. We first evaluated three representative classes of lipid modified immunostimulatory CpG ODNs. All lipo CpG ODNs considerably drained to LNs more than unmodified CpG ODNs, while they appeared to be functionally compromised in in vitro immune activation. However, administration of lipo CpG class B and C ODNs, not lipo CpG class A ODN, with protein antigen in mice led to improved antigen-specific CD8+ T cell responses and humoral responses relative to their parent compounds. We then evaluated the therapeutic efficacy of immunosuppressive ODN A151 and its lipid modified form in inhibiting TLR9-mediated immune activation. The data showed that lipo ODN A151 was preferentially internalized by cells and accumulated in LNs in a larger magnitude compared to unmodified ODN A151. More importantly, prophylactic administration of lipo ODN A151, but not unmodified ODN A 151, resulted in profound inhibition of immune responses challenged and induced with CpG-adjuvanted vaccines. Next, we investigated structure-dependent stability of lipid modified amphiphilic polymers on red blood cells (RBCs). We revealed that longer lipid chain was preferred for more stable insertion on RBCs surface ex vivo, while shorter polyethylene glycerol (PEG) spacer conjugated amphiphiles exhibited more stable retention on RBCs in vivo. Moreover, cationic amphiphiles constructed with cationic lipids resulted in significantly prolonged circulation half-life on RBCs in vivo. Finally, we discovered a novel adjuvant enhancer which improved the adjuvant activities of TLR7/8 in vitro and in vivo. We found that certain amphiphilic oligonucleotides could improve TLR7 ligand induced NF-kB activation in the presence of albumin protein. In vivo, administration of imiquimod-adjuvanted vaccine mixed with structurally optimized amphiphilic oligonucleotide-based adjuvant booster induced markedly increased frequency of antigen-specific CD 8+ T cells and production of antigen-specific IgG in mice, while the same vaccine without adjuvant booster showed no effect. Thus, lipid functionalized oligonucleotide-based adjuvants booster could greatly improve immunogenicity of subunit vaccines. Collectively, lipid functionalized oligonucleotides not only accumulate in LNs by hitchhiking endogenous albumin, but also versatilely modulate the immune responses. Amphiphilic oligonucleotides may be broadly applicable for diseases involving the immune system, where immunomodulation is needed.

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