STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade

Juan Fu, David B. Kanne, Meredith Leong, Laura Hix Glickman, Sarah M. McWhirter, Edward Lemmens, Ken Mechette, Justin J. Leong, Peter Lauer, Weiqun Liu, Kelsey E. Sivick, Qi Zeng, Kevin C. Soares, Lei Zheng, Daniel A. Portnoy, Joshua J. Woodward, Andrew Mark Pardoll, Thomas W. Dubensky, Young Kim

Research output: Contribution to journalArticle

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-kB (nuclear factor kB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce robust type I interferon and proinflammatory cytokine responses. CDN ligandswere formulatedwith granulocyte-macrophage colony-stimulating factor (GMCSF)-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 onewith an Rp,Rp dithio diastereomer and noncanonical c[A(2′,5′)pA(3′,5′)p] phosphate bridge zstructure, enhanced antitumor efficacy of STINGVAXinmultiple aggressive therapeuticmodels of established cancer inmice.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 (programmeddeathligand1)up-regulation, which was associatedwith 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.

Original languageEnglish (US)
Article number283ra52
JournalScience Translational Medicine
Volume7
Issue number283
DOIs
StatePublished - Apr 15 2015

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Cancer Vaccines
Interferons
Genes
Neoplasms
STAT6 Transcription Factor
Interferon Regulatory Factor-3
T-Lymphocytes
Interferon Type I
Neoplasm Antigens
Granulocyte-Macrophage Colony-Stimulating Factor
Dendritic Cells
Up-Regulation
Phosphates
Cytokines

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fu, J., Kanne, D. B., Leong, M., Glickman, L. H., McWhirter, S. M., Lemmens, E., ... Kim, Y. (2015). STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Science Translational Medicine, 7(283), [283ra52]. https://doi.org/10.1126/scitranslmed.aaa4306

STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. / Fu, Juan; Kanne, David B.; Leong, Meredith; Glickman, Laura Hix; McWhirter, Sarah M.; Lemmens, Edward; Mechette, Ken; Leong, Justin J.; Lauer, Peter; Liu, Weiqun; Sivick, Kelsey E.; Zeng, Qi; Soares, Kevin C.; Zheng, Lei; Portnoy, Daniel A.; Woodward, Joshua J.; Pardoll, Andrew Mark; Dubensky, Thomas W.; Kim, Young.

In: Science Translational Medicine, Vol. 7, No. 283, 283ra52, 15.04.2015.

Research output: Contribution to journalArticle

Fu, J, Kanne, DB, Leong, M, Glickman, LH, McWhirter, SM, Lemmens, E, Mechette, K, Leong, JJ, Lauer, P, Liu, W, Sivick, KE, Zeng, Q, Soares, KC, Zheng, L, Portnoy, DA, Woodward, JJ, Pardoll, AM, Dubensky, TW & Kim, Y 2015, 'STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade', Science Translational Medicine, vol. 7, no. 283, 283ra52. https://doi.org/10.1126/scitranslmed.aaa4306
Fu, Juan ; Kanne, David B. ; Leong, Meredith ; Glickman, Laura Hix ; McWhirter, Sarah M. ; Lemmens, Edward ; Mechette, Ken ; Leong, Justin J. ; Lauer, Peter ; Liu, Weiqun ; Sivick, Kelsey E. ; Zeng, Qi ; Soares, Kevin C. ; Zheng, Lei ; Portnoy, Daniel A. ; Woodward, Joshua J. ; Pardoll, Andrew Mark ; Dubensky, Thomas W. ; Kim, Young. / STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. In: Science Translational Medicine. 2015 ; Vol. 7, No. 283.
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AU - Leong, Meredith

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AU - Lemmens, Edward

AU - Mechette, Ken

AU - Leong, Justin J.

AU - Lauer, Peter

AU - Liu, Weiqun

AU - Sivick, Kelsey E.

AU - Zeng, Qi

AU - Soares, Kevin C.

AU - Zheng, Lei

AU - Portnoy, Daniel A.

AU - Woodward, Joshua J.

AU - Pardoll, Andrew Mark

AU - Dubensky, Thomas W.

AU - Kim, Young

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