2. Academic Validation
  3. STING agonist 8803 reprograms the immune microenvironment and increases survival in preclinical models of glioblastoma

STING agonist 8803 reprograms the immune microenvironment and increases survival in preclinical models of glioblastoma

  • J Clin Invest. 2024 Jun 17;134(12):e175033. doi: 10.1172/JCI175033.
Hinda Najem 1 2,  Spencer T Lea 3,  Shashwat Tripathi 1 2,  Lisa Hurley 1 2,  Chao-Hsien Chen 4,  Ivana William 3,  Moloud Sooreshjani 1 2,  Michelle Bowie 5,  Genevieve Hartley 3,  Corey Dussold 1 2,  Sebastian Pacheco 1 2,  Crismita Dmello 1 2,  Catalina Lee-Chang 1 2,  Kathleen McCortney 1 2,  Alicia Steffens 1 2,  Jordain Walshon 1 2,  Martina Ott 6,  Jun Wei 3,  Anantha Marisetty 7,  Irina Balyasnikova 1 2,  Roger Stupp 1 2,  Rimas V Lukas 2 8,  Jian Hu 9,  Charles David James 1 2,  Craig M Horbinski 1 2,  Maciej S Lesniak 1 2,  David M Ashley 5,  Waldemar Priebe 10 11,  Leonidas C Platanias 12,  Michael A Curran 3,  Amy B Heimberger 1 2
Affiliations

Affiliations

  • 1 Department of Neurological Surgery and.
  • 2 Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
  • 3 Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 4 Department of Neurology, Houston Methodist Neurological Institute, Houston, Texas, USA.
  • 5 Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.
  • 6 Miltenyi Biotec, Bergisch Gladbach, Germany.
  • 7 Immatics US, Houston, Texas, USA.
  • 8 Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
  • 9 Department of Cancer Biology and.
  • 10 Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
  • 11 Moleculin, Houston, Texas, USA.
  • 12 Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
PMID: 38941297 DOI: 10.1172/JCI175033
Abstract

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 and iNOS, while decreasing immunosuppressive CD206 and Arginase. In humanized mice, where tumor cell STING is epigenetically silenced, 8803 therapeutic activity was maintained, further attesting to myeloid dependency and reprogramming. Although the combination with a STAT3 Inhibitor did not further enhance STING agonist activity, the addition of anti-PD-1 Antibodies to 8803 treatment enhanced survival in an immune checkpoint blockade-responsive glioma model. In summary, 8803 as a monotherapy demonstrates marked in vivo therapeutic activity, meriting consideration for clinical translation.

Keywords

Brain cancer; Cancer immunotherapy; Immunology; Oncology; Signal transduction.

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