Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors
Background Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly i...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2024-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/4/e008547.full |
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| author | Nicholas Waldron P Rod Dunbar Sanjeev Deva Oh Kyu Yoon John Ling Kai-Wen Lin Dung Thai Latesh Lad Ahmed A Othman Jared M Odegard Adele Y Wang Jonathan Nazareno Edmond Ang |
| author_facet | Nicholas Waldron P Rod Dunbar Sanjeev Deva Oh Kyu Yoon John Ling Kai-Wen Lin Dung Thai Latesh Lad Ahmed A Othman Jared M Odegard Adele Y Wang Jonathan Nazareno Edmond Ang |
| author_sort | Nicholas Waldron |
| collection | DOAJ |
| description | Background Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly in combination regimens, and allow flexible management of immune-mediated toxicities.Methods PD-L1 binding activity was assessed in engineered dimerization and primary cell target occupancy assays. Preclinical antitumor activity was evaluated in ex vivo and in vivo human PD-L1-expressing tumor models. Human safety, tolerability, pharmacokinetics, and biomarker activity were evaluated in an open-label, multicenter, sequential dose-escalation study in patients with advanced solid tumors. Biomarkers evaluated included target occupancy, flow cytometric immunophenotyping, plasma cytokine measurements, and T-cell receptor sequencing.Results GS-4224 binding caused dimerization of PD-L1, blocking its interaction with PD-1 and leading to reversal of T-cell inhibition and increased tumor killing in vitro and in vivo. The potency of GS-4224 was dependent on the density of cell surface PD-L1, with binding being most potent on PD-L1–high cells. In a phase 1 dose-escalation study in patients with advanced solid tumors, treatment was well tolerated at doses of 400–1,500 mg once daily. Administration of GS-4224 was associated with a dose-dependent increase in plasma GS-4224 exposure and reduction in free PD-L1 on peripheral blood T cells, an increase in Ki67 among the PD-1-positive T-cell subsets, and elevated plasma cytokines and chemokines.Conclusions GS-4224 is a novel, orally bioavailable small molecule inhibitor of PD-L1. GS-4224 showed evidence of expected on-target biomarker activity, including engagement of PD-L1 and induction of immune-related pharmacodynamic responses consistent with PD-L1 blockade.Trial registration number NCT04049617. |
| format | Article |
| id | doaj-art-2b728df121a442dc8e3c4516f01ebf5f |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-2b728df121a442dc8e3c4516f01ebf5f2024-11-14T02:45:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-04-0112410.1136/jitc-2023-008547Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumorsNicholas Waldron0P Rod Dunbar1Sanjeev Deva2Oh Kyu Yoon3John Ling4Kai-Wen Lin5Dung Thai6Latesh Lad7Ahmed A Othman8Jared M Odegard9Adele Y Wang10Jonathan Nazareno11Edmond Ang12University of Auckland, Auckland, New ZealandSchool of Biological Sciences and Maurice Wilkins Centre, The University of Auckland, Auckland, New ZealandUniversity of Auckland, Auckland, New ZealandGilead Sciences, Inc, Foster City, California, USAGilead Sciences, Inc, Foster City, California, USAGilead Sciences, Inc, Foster City, California, USAGilead Sciences, Inc, Foster City, California, USAGilead Sciences, Inc, Foster City, California, USAClinical Pharmacology, Gilead Sciences Inc, Foster City, California, USABiomarker Sciences, Gilead Sciences Inc, Seattle, Washington, USAGilead Sciences, Inc, Foster City, California, USAGilead Sciences, Inc, Foster City, California, USAUniversity of Auckland, Auckland, New ZealandBackground Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies in a range of immunogenic cancer types. Blocking this pathway with an oral therapy could benefit patients through greater convenience, particularly in combination regimens, and allow flexible management of immune-mediated toxicities.Methods PD-L1 binding activity was assessed in engineered dimerization and primary cell target occupancy assays. Preclinical antitumor activity was evaluated in ex vivo and in vivo human PD-L1-expressing tumor models. Human safety, tolerability, pharmacokinetics, and biomarker activity were evaluated in an open-label, multicenter, sequential dose-escalation study in patients with advanced solid tumors. Biomarkers evaluated included target occupancy, flow cytometric immunophenotyping, plasma cytokine measurements, and T-cell receptor sequencing.Results GS-4224 binding caused dimerization of PD-L1, blocking its interaction with PD-1 and leading to reversal of T-cell inhibition and increased tumor killing in vitro and in vivo. The potency of GS-4224 was dependent on the density of cell surface PD-L1, with binding being most potent on PD-L1–high cells. In a phase 1 dose-escalation study in patients with advanced solid tumors, treatment was well tolerated at doses of 400–1,500 mg once daily. Administration of GS-4224 was associated with a dose-dependent increase in plasma GS-4224 exposure and reduction in free PD-L1 on peripheral blood T cells, an increase in Ki67 among the PD-1-positive T-cell subsets, and elevated plasma cytokines and chemokines.Conclusions GS-4224 is a novel, orally bioavailable small molecule inhibitor of PD-L1. GS-4224 showed evidence of expected on-target biomarker activity, including engagement of PD-L1 and induction of immune-related pharmacodynamic responses consistent with PD-L1 blockade.Trial registration number NCT04049617.https://jitc.bmj.com/content/12/4/e008547.full |
| spellingShingle | Nicholas Waldron P Rod Dunbar Sanjeev Deva Oh Kyu Yoon John Ling Kai-Wen Lin Dung Thai Latesh Lad Ahmed A Othman Jared M Odegard Adele Y Wang Jonathan Nazareno Edmond Ang Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors Journal for ImmunoTherapy of Cancer |
| title | Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors |
| title_full | Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors |
| title_fullStr | Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors |
| title_full_unstemmed | Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors |
| title_short | Oral PD-L1 inhibitor GS-4224 selectively engages PD-L1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors |
| title_sort | oral pd l1 inhibitor gs 4224 selectively engages pd l1 high cells and elicits pharmacodynamic responses in patients with advanced solid tumors |
| url | https://jitc.bmj.com/content/12/4/e008547.full |
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