Design and development of an injectable, polymer-based immune priming center




Singh, Ankur

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Immunotherapy, as a strategy to trigger immunity and eradicate a variety of chronic infectious diseases and cancers, has been explored for several decades with significant success in animal models. However, effective translation of these strategies into human clinical settings has proven elusive. Several cell-based anti-tumor therapies have progressed to clinical trials where antigen presenting dendritic cells (DCs) are isolated from patients, loaded with viral or tumor antigens and infused back in the patients. These ex-vivo “trained” DCs then present antigens to naïve T cells (adoptive therapy). However there exist several major limitations to this approach, including morbidity associated with patient cell isolation, high cost of ex vivo cell manipulation, time lag in “training” the immune cells, regulatory concerns, as well as the fact that ~ 90% of transplanted DCs die before they even home to lymph nodes. On the other hand, current immunotherapy approaches using recombinant proteins, synthetic peptides or nucleic acids, which "train" the immune cells in vivo to mount an immune response, have failed to address the tremendous challenge in generating efficient, sustained and protective immunity. There are two major challenges that must be overcome, (a) there exist relatively fewer numbers of immune cells at the sites of vaccine administration and given that these antigens themselves are weakly immunogenic, vaccine formulations must be tailored to attract large number of DCs to the immunization site and (b) immunologically, conventional nucleic acid or protein/peptide based vaccines do not elicit the required T helper type (Th) immunity along with a strong Cytotoxic T Lymphocyte (CTL) response against viral or tumor antigens and therefore new formulations must be able to “direct” the immune response towards a specific Th-type. Our goal was to design polymer-based sustained release formulations to addresses these challenges. Specifically, we have designed and developed delivery systems that can carry multiple biomolecules (nucleic acids, proteins, peptides, and chemoattractants) in a single injectable formulation. The delivery system promoted efficient migration of a large number of DCs to the site of injection and successful delivery of antigen resulting in activation of DCs. The multi-modal delivery system has the ability to bias or switch the immune response to the desired phenotype (e.g. Th1 or Th2) in a controlled manner. Using an infectious disease model against hepatitis B we have shown that co-encapsulation of Interleukin-10 (IL10) cytokine targeted siRNA within polymeric, surface-functionalized microparticles can further enhance DC activation and T cell proliferation in vitro as well as switch the hepatitis-specific immune response towards a strong Th1 phenotype in vivo. Further, in a weakly immunogenic A20 B cell lymphoma mouse model, a combination of microparticles and chemokine releasing in situ crosslinkable hydrogel provided significant Th1 type cellular immune response and delayed the onset of tumor development. Thus, the in situ crosslinkable hydrogel co-delivering microparticles and DC attracting chemokines creates an immune priming center with broad applications in a variety of disease models.


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