STING-induced blood-brain barrier opening combined with radiotherapy potentiates antitumor response in a high-grade glioma model
Shashwat Tripathi, Hinda Najem, Lisa Hurley, Ruochen Du, Crismita Dmello, Heba Ali, Kathleen McCortney, Karl J. Habashy, Peng Zhang, Craig M. Horbinski, Lara Leoni, Ryan J. Avery, Rimas V. Lukas, Timothy L. Sita, David R. Raleigh, Sean Sachdev, Roger Stupp, Maciej S. Lesniak, David M. Ashley, Daniele Procissi, Michael A. Curran, Irina Balyasnikova, Amy B. Heimberger
Shashwat Tripathi, Hinda Najem, Lisa Hurley, Ruochen Du, Crismita Dmello, Heba Ali, Kathleen McCortney, Karl J. Habashy, Peng Zhang, Craig M. Horbinski, Lara Leoni, Ryan J. Avery, Rimas V. Lukas, Timothy L. Sita, David R. Raleigh, Sean Sachdev, Roger Stupp, Maciej S. Lesniak, David M. Ashley, Daniele Procissi, Michael A. Curran, Irina Balyasnikova, Amy B. Heimberger
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Research Article Immunology Oncology Vascular biology

STING-induced blood-brain barrier opening combined with radiotherapy potentiates antitumor response in a high-grade glioma model

Abstract

Radiation therapy (RT) is the standard of care for glioblastoma but is not curative. Triggering the cGAS/stimulator of interferon genes (STING) pathway with potent agonists, such as 8803, exerts activity across high-grade glioma preclinical models. To determine if the combination of 8803 with RT warrants consideration in the up-front treatment setting and to clarify the underlying mechanisms of therapeutic activity, C57BL/6J mice harboring intracerebral CT-2A or QPP8v gliomas were treated with RT, intratumoral 8803, or both. The treatment with the combination resulted in 80% long-term survival in the CT-2A model but not in the radiation-resistant QPP8v model. This therapeutic effect was maintained in Sting–/– CT-2A cells, highlighting the direct role of the immune system in mediating the survival benefit. Single-cell RNA-Seq identified increased nitric oxide synthase 2 (Nos2) in inflammatory tumor-associated macrophages; however, the therapeutic effect was maintained in Nos2–/– mice. Additionally, 8803 reprogrammed the blood-brain barrier (BBB) by altering the Pecam and Cd147 pathways in endothelial cells; intracranial injection of 8803 induced bihemispheric BBB opening for up to 24 hours. Sting activation was visualized longitudinally using 3’-deoxy-3’-[18F]-fluorothymidine ([18F]-FLT) PET, which peaked 72–96 hours after 8803 administration. In summary, 8803 combined with RT triggers distinctive antiglioma immune reactivity, facilitates BBB opening, and warrants consideration for up-front clinical trials in glioblastoma, where treatment effects can be monitored using [18F]-FLT PET imaging.

Authors

Shashwat Tripathi, Hinda Najem, Lisa Hurley, Ruochen Du, Crismita Dmello, Heba Ali, Kathleen McCortney, Karl J. Habashy, Peng Zhang, Craig M. Horbinski, Lara Leoni, Ryan J. Avery, Rimas V. Lukas, Timothy L. Sita, David R. Raleigh, Sean Sachdev, Roger Stupp, Maciej S. Lesniak, David M. Ashley, Daniele Procissi, Michael A. Curran, Irina Balyasnikova, Amy B. Heimberger

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Figure 6

8803 in vivo activity determined using [18F]-FLT PET imaging.

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8803 in vivo activity determined using [18F]-FLT PET imaging. Representa...
Representative MRI and [18F]-FLT PET merged axial and coronal images of mouse brains implanted with CT-2A gliomas analyzed at baseline (time 0) and 96 hours (4 days) in control (A) and after 8803 treatment (B). %ID, percentage of injected dose. (C) Baseline [18F]-FLT uptake in control (n = 5) and 8803-treated CT-2A glioma (n = 5). Error bars show the standard error of the mean. There was no significant difference. (D) Change in [18F]-FLT uptake at 48 and 96 hours in control versus 8803 animals. * < 0.05; **** < 0.0001. (E) Percentage change in tumor volume as measured on MRI between baseline and 48 or 96 hours. ** < 0.01. (F) Quantification of Ki-67+ proliferating tumor cells between control (N = 3) versus 8803 (n = 6). A total of 3 ROIs per tumor were chosen. (G) Baseline [18F]-FLT uptake in control (n = 4) and 8803-treated CT-2A STING-KO glioma (n = 3). Error bars show the standard error of the mean. (H) Change in [18F]-FLT uptake at 72 hours in control versus 8803 animals. ** < 0.01. (I) Percentage change in tumor volume as measured on MRI between baseline and 72 hours. * < 0.05. Panels C–E and G–I were analyzed using the Wilcoxon rank-sum test.