| dc.description.abstract | The development of cancer occurs when immunosuppression inhibits the naturally occurring process through which the immune system recognizes and eliminates cancer cells (i.e. the cancer-immunity-cycle). While clinically used strategies to lessen immunosuppression, such as immune checkpoint blockade, can be extraordinarily effective at eliminating cancer and preventing disease recurrence, they currently only work in patients who already possess a certain degree of antitumor immunity. This dissertation describes the development of novel platforms for local immunomodulation, which were designed to address those limitations of the current standard-of-care cancer immunotherapies. Utilizing water-in-oil-in-water (w/o/w) double emulsion synthesis with ammonium bicarbonate as a porogen, porous poly(lactic-co-glycolic acid) (PLGA) microparticles were engineered for the local delivery of cytosol-penetrating nanoparticles, comprising a pH-responsive, endosomolytic diblock copolymer (i.e. D-PDB) and small interfering RNA. The PLGA microparticles controlled and sustained the release of nanoparticles targeting RNA interference while preserving their functionality, as demonstrated by longitudinal luminescence knockdown in a murine tumor model that constitutively expresses luciferase. Next, the development of a nanoparticulate innate immune activator (i.e. NanoISD) targeting the cGAS/STING cellular signaling pathway is described. NanoISD comprises D-PDB loaded with a synthetic cGAS ligand. Notably, NanoISD overcomes several delivery barriers to activate the cGAS enzyme in the cytosol of tumor cells and thereby stimulate innate immunity. Intratumoral treatment of NanoISD in murine tumor models resulted in increased tumor infiltration of natural killer cells and T cells, attenuated tumor growth, prolonged survival, and improved responses to immune checkpoint blockade. Lastly, another nanoparticulate innate immune activator (i.e. AluNPs) is reported. Similar to NanoISD, AluNPs were formulated with D-PDB, but instead were loaded with endogenous Alu RNA elements that can trigger the RIG-I and TLR3 cellular signaling pathways to stimulate innate immunity. Upon intratumoral administration of AluNPs in a murine tumor model, interferon production within the tumor cell compartment was initiated and tumor burden was significantly reduced. Collectively, these platforms provide novel strategies for the immunotherapeutic treatment of solid tumor cancers. | |
