Intratumoral immunotherapy with STING agonist, ADU-S100, induces CD8+ T-cell mediated anti-tumor immunity in an esophageal adenocarcinoma model
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Ali H. Zaidi1,*, Ronan J. Kelly2,*, Anastasia Gorbunova1, Ashten N. Omstead1, Madison S. Salvitti1, Ping Zheng1, Juliann E. Kosovec1, Soyoung Lee3, Shahin Ayazi1, Laila Babar1, Gene G. Finley1, Ajay Goel4 and Blair A. Jobe1
1 Esophageal and Lung Institute, Allegheny Health Network, Pittsburgh, PA, USA
2 Department of Hematology and Oncology, Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
3 Department of Radiation Oncology, Allegheny Health Network, Pittsburgh, PA, USA
4 Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA, USA
* Co-first authors and contributed equally to this work
|Ali H. Zaidi,||email:||[email protected]|
Keywords: esophageal adenocarcinoma; STING; PD-L1; CD8+ T-cells; IFNβ
Received: November 20, 2020 Accepted: January 26, 2021 Published: February 16, 2021
Background: Esophageal adenocarcinoma (EAC) is a deadly disease with limited treatment options. STING is a transmembrane protein that activates transcription of interferon genes, resulting in stimulation of APCs and enhanced CD8+ T-cell infiltration. The present study evaluates STING agonists, alone and in combination with radiation to determine durable anticancer activity in solid tumors.
Materials and Methods: Esophagojejunostomy was performed on rats to induce reflux leading to the development of EAC. At 32 weeks post operatively, rats received intratumorally either 50 μg STING (ADU-S100) or placebo (PBS), +/– 16Gy radiation. Drug activity was evaluated by pre- and post- treatment MRI, histology, immunofluorescence and RT-PCR.
Results: Mean MRI tumor volume decreased by 30.1% and 50.8% in ADU-S100 and ADU-S100 + radiation animals and increased by 76.7% and 152.4% in placebo and placebo + radiation animals, respectively (P < 0.0001). Downstream gene expression, pre- to on- and post- treatment, demonstrated significant upregulation of IFNβ, TNFα, IL-6, and CCL-2 in the treatment groups vs. placebo. On- or post- treatment, radiation alone, ADU-S100 alone, and ADU-S100 + radiation groups demonstrated enhanced PD-LI expression, induced by upregulation of CD8+ T-cells (p < 0.01).
Conclusions: ADU-S100 +/– radiation exhibits potent antitumor activity and a promising immunomodulatory profile in a de novo EAC.
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