STING agonist 8803 reprograms the immune microenvironment and increases survival in preclinical models of glioblastoma
Hinda Najem, … , Michael A. Curran, Amy B. Heimberger
Hinda Najem, … , Michael A. Curran, Amy B. Heimberger
Published June 17, 2024
Citation Information: J Clin Invest. 2024;134(12):e175033. https://doi.org/10.1172/JCI175033.
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Research Article Immunology Oncology

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

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.

Authors

Hinda Najem, Spencer T. Lea, Shashwat Tripathi, Lisa Hurley, Chao-Hsien Chen, Ivana William, Moloud Sooreshjani, Michelle Bowie, Genevieve Hartley, Corey Dussold, Sebastian Pacheco, Crismita Dmello, Catalina Lee-Chang, Kathleen McCortney, Alicia Steffens, Jordain Walshon, Martina Ott, Jun Wei, Anantha Marisetty, Irina Balyasnikova, Roger Stupp, Rimas V. Lukas, Jian Hu, Charles David James, Craig M. Horbinski, Maciej S. Lesniak, David M. Ashley, Waldemar Priebe, Leonidas C. Platanias, Michael A. Curran, Amy B. Heimberger

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Figure 7

Dose and schedule adjustments for combinatorial WP1066 with 8803: combination with anti–PD-1.

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Dose and schedule adjustments for combinatorial WP1066 with 8803: combin...
(A) Schema of the treatment of immunocompetent mice that underwent i.c. implantation of either GL261 or CT-2A glioma cells. (B) The survival rate estimated by the Kaplan-Meier method of C57BL/6J mice implanted with GL261 and CT-2A. For the GL261 survival: control: 10 mice (median survival [MS]: 25 days), WP1066: 10 mice (MS: 30 days), 8803: 14 mice (MS: 30 days; 5 long-term survivors), WP1066 + 8803: 16 mice (MS: 71 days; 8 long-term survivors). Statistics (log-rank test): control versus WP1066 P = 0.04; control versus 8803 P = 0.01; control versus WP1066 + 8803 P < 0.0001; WP1066 versus WP1066 + 8803 P = 0.006; 8803 versus WP1066 + 8803 P = 0.32. For the CT-2A survival: control: 10 mice (MS: 28 days), WP1066: 9 mice (MS: 28 days), 8803: 14 mice (MS: 50 days; 7 long-term survivors), WP1066 + 8803: 16 mice (MS: 48 days; 8 long-term survivors). Statistics (log-rank test): control versus WP1066 P = 0.57; control versus 8803 P < 0.0001; control versus WP1066 + 8803 P < 0.0001; WP1066 versus WP1066 + 8803 P < 0.001; 8803 versus WP1066 + 8803 P = 0.95. (C) Schema of the treatment of immunocompetent mice that underwent i.c. implantation of either CT-2A or QPP8v (subclone) glioma cells. QPP8v tumors received 8803 (5 μg/mouse i.c. on days 7 and 17), anti–PD-1 (25 μg i.c. on days 7 and 17), and vehicle control (PBS) or anti–PD-1 (250 μg i.p. on days 7, 10, and 13) in single and combination therapies. (D) The survival rate estimated by the Kaplan-Meier method of C57BL/6J mice implanted with CT-2A and QPP8. For CT-2A: IgG: 10 mice (MS: 30 days); anti–PD-1: 10 mice (MS: 35 days), 8803: 10 mice (MS: 56 days, 4 long-term survivors); 8803 + anti–PD-1: 10 mice (MS: undefined, 8 long-term survivors); 8803 + IgG: 10 mice (MS: 65.5 days, 5 long-term survivors). Statistics (log-rank test): IgG versus anti–PD-1 P = 0.04; IgG versus 8803 P < 0.01; IgG versus 8803 + anti–PD-1 P < 0.0001; anti–PD-1 versus 8803 + anti–PD-1 P < 0.001; 8803 versus 8803 + anti–PD-1 P = 0.04; 8803 + IgG versus 8803 + anti–PD-1 P = 0.12. For QPP8: PBS: 10 mice (MS: 47 days); anti–PD-1: 10 mice (MS: 55 days); 8803: 10 mice (MS: 76 days, 4 long-term survivors); 8803 + anti–PD-1 (i.p.): 10 mice (MS: 95.5 days, 3 long-term survivors); 8803 + anti–PD-1 (i.c.): 10 mice (MS: 111 days, 5 long-term survivors). Statistics (log-rank test): PBS versus anti–PD-1 P = 0.164; PBS versus 8803 P < 0.0001; PBS versus 8803 + anti–PD-1 (i.p.) P = 0.0006; PBS versus 8803 + anti–PD-1 (i.c.) P < 0.0001; anti–PD-1 versus 8803 P < 0.0001; anti–PD-1 versus 8803 + anti–PD-1 (i.p.) P = 0.002; anti–PD-1 versus 8803 + anti–PD-1 (i.c.) P < 0.0001; 8803 versus 8803 + anti–PD-1 (i.c.) P = 0.57; 8803 versus 8803 + anti–PD-1 (i.p.) P = 0.85. (E) Multiplexed sequential immunofluorescence images of untreated CT-2A gliomas (n = 3). Forty-eight hours after either the first (day 9) or second dose (day 16) of 8803, animals were euthanized and the brains were imaged for the following (n = 3/group): DAPI (dark blue), GFAP (light blue), CD31 (cyan blue), STING (red), p-IRF3 (pink), CD4+ (yellow), and CD8+ (white) T cells. White boxes outline the portion shown at higher magnification in the right column of images. Scale bars: 500 μm (left 3 columns) and 50 μm (right column).