Design and Optimization of ‘Smart’ Nanoparticles for Targeting of the STING Pathway with Applications in Cancer Immunotherapy

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.