Development of small molecule STING agonists that can evoke host anti-cancer immune defences following local or systemic delivery
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Author(s)
Haynes, Nicole
Connor, Theresa
Morrow, Ben
Doherty, Judy
Dennis, Matthew
Hubert, Jonathan
Spall, Sukhdeep
Cuzzupe, Anthony
White, Karen
Charman, Susan
Lock, Aaron
Avery, Vicky
Nuttall, Stewart
Peat, Tom
Dolezal, Olan
Pilling, Pat
Revalde, Jezrael
Yow, Tin
Arndt, Greg
Falk, Hendrik
Devlin, Mark
Street, Ian
Khoo, Poh
Stupple, Paul
Monahan, Brendon
Griffith University Author(s)
Year published
2019
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Background:
STING is a ubiquitously expressed innate immune sensor which is essential for the production of host defence-related proteins including type I interferons and proinflammatory cytokines that promote the recruitment and effector activity of innate and adaptive immune cells [1]. Targeted activation of STING and the associated release of type I interferons can enhance the sensitivity of antigen presenting cells to neoantigens and promote their ability to prime T cell-based anti-cancer immune responses [1,2]. This can lead to the establishment of T cell inflamed tumor microenvironments that are more susceptible to ...
View more >Background: STING is a ubiquitously expressed innate immune sensor which is essential for the production of host defence-related proteins including type I interferons and proinflammatory cytokines that promote the recruitment and effector activity of innate and adaptive immune cells [1]. Targeted activation of STING and the associated release of type I interferons can enhance the sensitivity of antigen presenting cells to neoantigens and promote their ability to prime T cell-based anti-cancer immune responses [1,2]. This can lead to the establishment of T cell inflamed tumor microenvironments that are more susceptible to the anti-tumor effects of checkpoint blockade therapy [3]. The Cancer Therapeutics CRC (CTx) is developing direct small molecule STING agonists that can be administered systemically as an adjunct to immune checkpoint antibody therapy. Methods: A phenotypic screen was run using an IRF3-luciferase reporter cell line looking for activation of Type I Interferon genes when screened against CTx small molecule libraries. Validated hits were deconvoluted by STING SPR to confirm direct STING binding. A mature medicinal chemistry program is underway with an established screening cascade including in vitro target engagement and primary cell functional assays, structural biology, in vivo PK/PD, and efficacy assays to determine mechanism(s) of action and demonstrate therapeutic index. Results: CTx has developed potent drug-like small molecule STING agonist compounds that show direct STING binding. Cellular activity is dependent upon STING (inactive in STING-/- cells), independent of cGAS (active in cGAS-/- cells), and can be blocked by TBK1 inhibitors. Compounds show activity in primary mouse and human cells across a range of STING variants. Dose-dependent in vivo PD biomarker responses, including increased plasma IFN-β levels, were seen when administered intravenously (I.V) or intratumorally (I.T). In vivo, single agent efficacy of CTx STING agonists has been tested in multiple syngeneic mouse models of solid cancer. Treatment via I.T or I.V administration was well tolerated and evoked therapeutically beneficial immune-mediated anti-tumor responses. Successful induction of immunological memory, in response to STING agonist treatment was demonstrated in tumor-rechallenge experiments. In less responsive models, where intermediate efficacy was observed, increased tumor growth control could be achieved by co-treating mice with our STING agonist and anti-PD-1 antibody therapy. Conclusions: CTx has a mature STING agonist program that has successfully produced direct STING activators that can promote primary DC function and elicit immune-mediated anti-tumor responses in mouse models of solid cancer.
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View more >Background: STING is a ubiquitously expressed innate immune sensor which is essential for the production of host defence-related proteins including type I interferons and proinflammatory cytokines that promote the recruitment and effector activity of innate and adaptive immune cells [1]. Targeted activation of STING and the associated release of type I interferons can enhance the sensitivity of antigen presenting cells to neoantigens and promote their ability to prime T cell-based anti-cancer immune responses [1,2]. This can lead to the establishment of T cell inflamed tumor microenvironments that are more susceptible to the anti-tumor effects of checkpoint blockade therapy [3]. The Cancer Therapeutics CRC (CTx) is developing direct small molecule STING agonists that can be administered systemically as an adjunct to immune checkpoint antibody therapy. Methods: A phenotypic screen was run using an IRF3-luciferase reporter cell line looking for activation of Type I Interferon genes when screened against CTx small molecule libraries. Validated hits were deconvoluted by STING SPR to confirm direct STING binding. A mature medicinal chemistry program is underway with an established screening cascade including in vitro target engagement and primary cell functional assays, structural biology, in vivo PK/PD, and efficacy assays to determine mechanism(s) of action and demonstrate therapeutic index. Results: CTx has developed potent drug-like small molecule STING agonist compounds that show direct STING binding. Cellular activity is dependent upon STING (inactive in STING-/- cells), independent of cGAS (active in cGAS-/- cells), and can be blocked by TBK1 inhibitors. Compounds show activity in primary mouse and human cells across a range of STING variants. Dose-dependent in vivo PD biomarker responses, including increased plasma IFN-β levels, were seen when administered intravenously (I.V) or intratumorally (I.T). In vivo, single agent efficacy of CTx STING agonists has been tested in multiple syngeneic mouse models of solid cancer. Treatment via I.T or I.V administration was well tolerated and evoked therapeutically beneficial immune-mediated anti-tumor responses. Successful induction of immunological memory, in response to STING agonist treatment was demonstrated in tumor-rechallenge experiments. In less responsive models, where intermediate efficacy was observed, increased tumor growth control could be achieved by co-treating mice with our STING agonist and anti-PD-1 antibody therapy. Conclusions: CTx has a mature STING agonist program that has successfully produced direct STING activators that can promote primary DC function and elicit immune-mediated anti-tumor responses in mouse models of solid cancer.
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Conference Title
Journal for ImmunoTherapy of Cancer
Volume
7
Copyright Statement
© The Author(s). 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Subject
Oncology and carcinogenesis
Science & Technology
Life Sciences & Biomedicine
Oncology
Immunology