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The Stimulator of Interferon Genes (STING) pathway represents a major innate immune sensing mechanism for tumor-derived DNA. Modified cyclic dinucleotides (CDNs) that mimic the endogenous STING ligand cGAMP are currently being explored in patients with solid tumors that amenable to intratumoral delivery. Inadequate bioavailability and insufficient lipophilicity are limiting factors for clinical CDN development, in particular when consideration is given to systemic administration approaches. We have shown that the formulation of oligonucleotides into Spherical Nucleic Acid (SNA) nanostructures, i.e., the presentation of oligonucleotides at high density on the surface of nanoparticle cores, lead to biochemical and biological properties that are radically different from those of linear oligonucleotides. First-generation SNAs conjugated with TLR9-agonsitic DNA oligonculeotides (NCT03086278; solid cancers) and intravenously administered, brain-penetrant siRNA-based SNAs (NCT03020017, recurrent GBM) have recently entered clinical trials. Here, we report the development of a STING-agonistic immunotherapy by targeting cGAS, the sensor of cytosolic dsDNA upstream of STING, with SNAs presenting dsDNA at high surface density. The strategy of using SNAs exploits the ability of cGAS to raise STING responses by delivering dsDNA and inducing the catalytic production of endogenous CDNs. SNA nanostructures carrying a 45bp IFN-simulating dsDNA oligonucleotide, the most commonly used and widely characterized cGAS activator, potently activated the cGAS-STING pathway, as evidenced by increased IRF responses, elevated protein marker expression indicative of the activated M1 macrophage state, and enhanced expression of pro-inflammatory cytokines in macrophage cultures in vitro, and in intracranial isogenic GBM explants in vivo. Our use of SNAs addresses the challenges of nucleic acid delivery to intracranial tumor sites, exploits the binding of closely-spaced, neighboring dsDNA molecules on the SNA surface to enhance the formation of a dimeric cGAS:DNA complex, and establishes cGAS-agonistic SNAs as a novel class of immune-stimulatory modalities for triggering innate immune responses against tumor.

DDIS-03. DEVELOPMENT OF A NOVEL CLASS OF cGAS AGONISTS TO TRIGGER STING PATHWAY-DEPENDENT INNATE IMMUNE RESPONSES AGAINST GLIOBLASTOMA