{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T11:48:59Z","timestamp":1793792939428,"version":"4.6.1"},"reference-count":25,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T00:00:00Z","timestamp":1740009600000},"content-version":"unspecified","delay-in-days":19,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Eisai Inc.","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2025,1,28]]},"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:p>E7766 is a novel stimulator of interferon genes (STING) agonist, capable of potent activation of immune cells and generating strong antitumor response in preclinical murine tumor models. Here we present the safety, efficacy, and biomarker results of the first-in-human phase I\/Ib study of intratumoral E7766 in patients with advanced solid tumors. Eligible patients with relapsing\/refractory cancers (n=24) were enrolled in dose-escalating cohorts to receive intratumoral injections of E7766 from 75 to 1000\u2009\u00b5g. The most frequent treatment-related treatment-emergent adverse events were chills (50.0%; 85.7%), fever (40.0%; 85.7%), and fatigue (30.0%; 35.7%) in patients who received non-visceral and visceral injections, respectively. Eight patients (33.3%) achieved stable disease as their best response per modified Response Evaluation Criteria In Solid Tumors version 1.1 with variability between injected and non-injected lesions. Plasma levels of IFN-\u03b1, IFN-\u03b2, IFN-\u03b3, TNF-\u03b1, IL-6, IP-10, MCP1, and MIP1b transiently increased in all evaluable patients within 10 hours postinjection, then dropped to baseline levels. Levels of blood and tumor gene expression increased in most interferon-related and STING genes tested. Further increases in programmed death ligand 1 and cluster of differentiation 8 expression at both the RNA and protein levels were also observed in some patients across dose levels. In total, E7766 generated on-target pharmacodynamic effects in patients with solid tumors. Further exploration in a homogeneous patient population is necessary to assess efficacy.<\/jats:p>","DOI":"10.1136\/jitc-2024-010511","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T19:05:29Z","timestamp":1740078329000},"page":"e010511","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":54,"title":["Phase I dose-escalation and pharmacodynamic study of STING agonist E7766 in advanced solid tumors"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct04144140","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1182-4908","authenticated-orcid":false,"given":"Jason J","family":"Luke","sequence":"first","affiliation":[{"name":"UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA"},{"name":"University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3529-0103","authenticated-orcid":false,"given":"David J","family":"Pinato","sequence":"additional","affiliation":[{"name":"Imperial College London, London, UK"},{"name":"University of Piemonte Orientale, Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dejan","family":"Juric","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"LoRusso","sequence":"additional","affiliation":[{"name":"Yale University School of Medicine, New Haven, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J","family":"Hosein","sequence":"additional","affiliation":[{"name":"University of Miami Leonard M. Miller School of Medicine, Miami, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupam M","family":"Desai","sequence":"additional","affiliation":[{"name":"Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1413-0079","authenticated-orcid":false,"given":"Robert","family":"Haddad","sequence":"additional","affiliation":[{"name":"Dana-Farber Cancer Institute, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"de Miguel","sequence":"additional","affiliation":[{"name":"START Madrid-HM CIOCC, Centro Integral Oncol\u00f3gico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3806-3691","authenticated-orcid":false,"given":"Andr\u00e9s","family":"Cervantes","sequence":"additional","affiliation":[{"name":"INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain"},{"name":"Instituto de Salud Carclos III. CIBERONC, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won Seog","family":"Kim","sequence":"additional","affiliation":[{"name":"Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5816-3019","authenticated-orcid":false,"given":"Aur\u00e9lien","family":"Marabelle","sequence":"additional","affiliation":[{"name":"University of Paris Saclay, Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Eisai Inc, Nutley, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanxin","family":"Rong","sequence":"additional","affiliation":[{"name":"Eisai Inc, Nutley, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8389-6059","authenticated-orcid":false,"given":"Xiaobin","family":"Yuan","sequence":"additional","affiliation":[{"name":"Eisai Inc, Nutley, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Champiat","sequence":"additional","affiliation":[{"name":"University of Paris Saclay, Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2025,2,20]]},"reference":[{"key":"2025100302190254000_13.2.e010511.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-0488-6"},{"key":"2025100302190254000_13.2.e010511.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.01.017"},{"key":"2025100302190254000_13.2.e010511.3","doi-asserted-by":"crossref","DOI":"10.3390\/cancers13112695","article-title":"STING Agonists as Cancer Therapeutics","volume":"13","author":"Amouzegar","year":"2021","journal-title":"Cancers (Basel)"},{"key":"2025100302190254000_13.2.e010511.4","doi-asserted-by":"crossref","DOI":"10.1038\/s41392-021-00554-y","article-title":"Cytosolic DNA sensing by cGAS: regulation, function, and human diseases","volume":"6","author":"Yu","year":"2021","journal-title":"Signal Transduct Target Ther"},{"key":"2025100302190254000_13.2.e010511.5","doi-asserted-by":"publisher","DOI":"10.7150\/thno.37574"},{"key":"2025100302190254000_13.2.e010511.6","doi-asserted-by":"crossref","first-page":"13316","DOI":"10.3390\/ijms241713316","article-title":"Significance of the cGAS-STING Pathway in Health and Disease","volume":"24","author":"Zhou","year":"2023","journal-title":"IJMS"},{"key":"2025100302190254000_13.2.e010511.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.04.031"},{"key":"2025100302190254000_13.2.e010511.8","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-1963"},{"key":"2025100302190254000_13.2.e010511.9","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.SABCS18-4456"},{"key":"2025100302190254000_13.2.e010511.10","first-page":"1740","article-title":"E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity","volume":"16","author":"Kim","year":"2021","journal-title":"ChemMedChem"},{"key":"2025100302190254000_13.2.e010511.11","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.SABCS18-3269"},{"key":"2025100302190254000_13.2.e010511.12","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-21-0780"},{"key":"2025100302190254000_13.2.e010511.13","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.cct.2017.04.006","article-title":"A Bayesian interval dose-finding design addressing Ockham\u2019s razor: mTPI-2","volume":"58","author":"Guo","year":"2017","journal-title":"Contemp Clin Trials"},{"key":"2025100302190254000_13.2.e010511.14","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-0220"},{"key":"2025100302190254000_13.2.e010511.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"2025100302190254000_13.2.e010511.16","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30074-8"},{"key":"2025100302190254000_13.2.e010511.17","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1312625"},{"key":"2025100302190254000_13.2.e010511.18","doi-asserted-by":"crossref","DOI":"10.1093\/annonc\/mdy424.015","article-title":"Preliminary results of the first-in-human (FIH) study of MK-1454, an agonist of stimulator of interferon genes (STING), as monotherapy or in combination with pembrolizumab (pembro) in patients with advanced solid tumors or lymphomas","volume":"29","author":"Harrington","year":"2018","journal-title":"Ann Oncol"},{"key":"2025100302190254000_13.2.e010511.19","doi-asserted-by":"crossref","unstructured":"Milhem M , Zakharia Y , Davar D , et al . 304\u2005Intratumoral injection of cmp-001, a toll-like receptor 9 (tlr9) agonist, in combination with pembrolizumab reversed programmed death receptor 1 (pd-1) blockade resistance in advanced melanoma. 35th Anniversary Annual Meeting (SITC 2020); November 2020 doi:10.1136\/jitc-2020-SITC2020.0304","DOI":"10.1136\/jitc-2020-SITC2020.0304"},{"key":"2025100302190254000_13.2.e010511.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.11.047"},{"key":"2025100302190254000_13.2.e010511.21","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2020-001906","article-title":"STING agonist-based treatment promotes vascular normalization and tertiary lymphoid structure formation in the therapeutic melanoma microenvironment","volume":"9","author":"Chelvanambi","year":"2021","journal-title":"J Immunother Cancer"},{"key":"2025100302190254000_13.2.e010511.22","doi-asserted-by":"crossref","DOI":"10.1186\/s12964-024-01860-y","article-title":"cGAS\/STING in skin melanoma: from molecular mechanisms to therapeutics","volume":"22","author":"Mahin","year":"2024","journal-title":"Cell Commun Signal"},{"key":"2025100302190254000_13.2.e010511.23","unstructured":"Glickman L , Skoble J , Rae C , et al . STACT-TREX1: A novel tumor-targeting systemically-delivered STING pathway agonist demonstrates robust anti-tumor efficacy in multiple murine cancer models. J Immunother Cancer 2018;6."},{"key":"2025100302190254000_13.2.e010511.24","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.SABCS18-5016"},{"key":"2025100302190254000_13.2.e010511.25","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-023-37217-1","article-title":"Epigenetic state determines the in vivo efficacy of STING agonist therapy","volume":"14","author":"Falahat","year":"2023","journal-title":"Nat Commun"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2024-010511","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T09:19:11Z","timestamp":1759483151000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2024-010511"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2]]},"references-count":25,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2,20]]},"published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1136\/jitc-2024-010511"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2024-010511","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2]]}}}