title: STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade.
abstract: Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and proinflammatory cytokine responses. CDN ligands were formulated with granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing cellular cancer vaccines--termed STINGVAX--that demonstrated potent in vivo antitumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including one with an Rp,Rp dithio diastereomer and noncanonical c[A(2',5')pA(3',5')p] phosphate bridge structure, enhanced antitumor efficacy of STINGVAX in multiple aggressive therapeutic models of established cancer in mice. Antitumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen-specific CD8(+) T cells. Tumors from STINGVAX-treated mice demonstrated marked PD-L1 (programmed death ligand 1) up-regulation, which was associated with tumor-infiltrating CD8(+)IFNγ(+) T cells. When combined with PD-1 (programmed death 1) blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone.
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD 21231, USA.
authors: Juan
authors: J
authors: Fu
authors: Aduro Biotech Inc., Berkeley, CA 94710, USA.
authors: David B
authors: DB
authors: Kanne
authors: Aduro Biotech Inc., Berkeley, CA 94710, USA.
authors: Meredith
authors: M
authors: Leong
authors: Aduro Biotech Inc., Berkeley, CA 94710, USA.
authors: Laura Hix
authors: LH
authors: Glickman
authors: Aduro Biotech Inc., Berkeley, CA 94710, USA.
authors: Sarah M
authors: SM
authors: McWhirter
authors: Aduro Biotech Inc., Berkeley, CA 94710, USA.
authors: Edward
authors: E
authors: Lemmens
authors: Aduro Biotech Inc., Berkeley, CA 94710, USA.
authors: Ken
authors: K
authors: Mechette
authors: Aduro Biotech Inc., Berkeley, CA 94710, USA.
authors: Justin J
authors: JJ
authors: Leong
authors: Aduro Biotech Inc., Berkeley, CA 94710, USA.
authors: Peter
authors: P
authors: Lauer
authors: Aduro Biotech Inc., Berkeley, CA 94710, USA.
authors: Weiqun
authors: W
authors: Liu
authors: Aduro Biotech Inc., Berkeley, CA 94710, USA.
authors: Kelsey E
authors: KE
authors: Sivick
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD 21231, USA.
authors: Qi
authors: Q
authors: Zeng
authors: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors: Kevin C
authors: KC
authors: Soares
authors: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors: Lei
authors: L
authors: Zheng
authors: Department of Molecular and Cell Biology and School of Public Health, University of California, Berkeley, Berkeley, CA 94720, USA.
authors: Daniel A
authors: DA
authors: Portnoy
authors: Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors: Joshua J
authors: JJ
authors: Woodward
authors: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors: Drew M
authors: DM
authors: Pardoll
authors: Aduro Biotech Inc., Berkeley, CA 94710, USA. ykim76@jhmi.edu tdubensky@adurobiotech.com.
authors: Thomas W
authors: TW
authors: Dubensky
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD 21231, USA. Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. ykim76@jhmi.edu tdubensky@adurobiotech.com.
authors: Young
authors: Y
authors: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D019496:Cancer Vaccines / Q000737:chemistry*; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins / Q000819:agonists*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D010710:Phosphates / Q000737:chemistry; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D000099197:STING Protein
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D007371:Interferon-gamma; D008024:Ligands; D008565:Membrane Proteins; D016328:NF-kappa B; D010710:Phosphates; D061026:Programmed Cell Death 1 Receptor; D017346:Protein Serine-Threonine Kinases; D050800:STAT6 Transcription Factor; C105992:PDCD1 protein, human; C494101:STAT6 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C403191:TBK1 protein, human