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Title page for ETD etd-03042019-120929


Type of Document Dissertation
Author Shae, Daniel
URN etd-03042019-120929
Title Design and Optimization of ‘Smart’ Nanoparticles for Targeting of the STING Pathway with Applications in Cancer Immunotherapy
Degree PhD
Department Chemical Engineering
Advisory Committee
Advisor Name Title
John T. Wilson Committee Chair
Jeffrey C. Rathell Committee Member
Justin M. Balko Committee Member
Paul E. Laibinis Committee Member
Scott A. Guelcher Committee Member
Keywords
  • Cancer Immunotherapy
Date of Defense 2019-02-19
Availability restrictone
Abstract
I detail the rational design and optimization of STING-NPs: a nanoparticle delivery platform that stimulates innate immunity and T cell activation through targeted activation of the stimulator of interferon genes (STING) protein, a critical cytosolic immune sensor of oncogenesis that has historically been difficult to target due to the poor pharmacokinetic properties of its natural ligand, cGAMP. STING-NPs comprise self-assembling, pH responsive, and endosomolytic polymers and overcome delivery barriers associated with cGAMP delivery by facilitating the cellular uptake and endosomal escape of cGAMP, facilitating a 2-3 order of magnitude enhancement in drug potency.

Administration of STING-NPs in murine tumor models initiates a multifaceted pro-inflammatory program associated with type I interferon expression and recruitment of T cells into the tumor microenvironment, eliciting tumor suppression or complete rejection through both intratumoral and systemic administration routes. Strikingly, STING-NP treatment is capable of mediating rejection of primary tumor growth as well as generating systemic and long-lived antitumor immunity, manifesting in suppression of distal tumor growth and resistance to cancer cell rechallenge. Efficacy is improved with the addition of checkpoint blockade antibodies, demonstrating that STING-NP treatment can sensitize tumors to ICB. Finally, the activity of STING-NPs is validated in an ex vivo model of freshly resected human melanoma.

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