{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T03:30:38Z","timestamp":1792899038836,"version":"4.5.0"},"reference-count":25,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T00:00:00Z","timestamp":1687996800000},"content-version":"unspecified","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020124","name":"Seagen Inc.","doi-asserted-by":"crossref","award":["There is no grant or award number to report for th"],"award-info":[{"award-number":["There is no grant or award number to report for th"]}],"id":[{"id":"10.13039\/100020124","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Merck Sharp & Dohme LLC","award":["There is no grant or award number to report for th"],"award-info":[{"award-number":["There is no grant or award number to report for th"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,5,26]]},"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG<jats:sub>1<\/jats:sub> antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating Fc\u03b3RIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3\u2009dose escalation at 0.6, 3, 10, 30, 45, and 60\u2009\u00b5g\/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion\/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily \u2264grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10\u201330\u2009\u00b5g\/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration number<\/jats:title>\n                  <jats:p>\n                     <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT02376699\">NCT02376699<\/jats:ext-link>.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2022-005584","type":"journal-article","created":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T14:00:14Z","timestamp":1688047214000},"page":"e005584","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas"],"prefix":"10.1136","volume":"11","clinical-trial-number":[{"clinical-trial-number":"nct02376699","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02376699","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02376699","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1710-5637","authenticated-orcid":false,"given":"Andrew L","family":"Coveler","sequence":"first","affiliation":[{"name":"Fred Hutchinson Cancer Center, Seattle, Washington, USA"},{"name":"University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C","family":"Smith","sequence":"additional","affiliation":[{"name":"University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tycel","family":"Phillips","sequence":"additional","affiliation":[{"name":"University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3948-2708","authenticated-orcid":false,"given":"Brendan D","family":"Curti","sequence":"additional","affiliation":[{"name":"Providence Cancer Center, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2798-7568","authenticated-orcid":false,"given":"Sanjay","family":"Goel","sequence":"additional","affiliation":[{"name":"Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amitkumar N","family":"Mehta","sequence":"additional","affiliation":[{"name":"The University of Alabama, Birmingham, Alabama, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M","family":"Kuzel","sequence":"additional","affiliation":[{"name":"Rush University Medical Center, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetomir N","family":"Markovic","sequence":"additional","affiliation":[{"name":"Mayo Clinic Minnesota, Rochester, Minnesota, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Rixe","sequence":"additional","affiliation":[{"name":"The University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L","family":"Bajor","sequence":"additional","affiliation":[{"name":"Case Western Reserve University, Cleveland, Ohio, USA"},{"name":"University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F","family":"Gajewski","sequence":"additional","affiliation":[{"name":"The University of Chicago Medical Center, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Gutierrez","sequence":"additional","affiliation":[{"name":"Hackensack University Medical Center, Hackensack, New Jersey, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hun Ju","family":"Lee","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay K","family":"Gopal","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Seattle, Washington, USA"},{"name":"University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Caimi","sequence":"additional","affiliation":[{"name":"Case Western Reserve University, Cleveland, Ohio, USA"},{"name":"University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth I","family":"Heath","sequence":"additional","affiliation":[{"name":"Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A","family":"Thompson","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Seattle, Washington, USA"},{"name":"University of Washington, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahar","family":"Ansari","sequence":"additional","affiliation":[{"name":"Seagen Inc, Bothell, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine","family":"Jacquemont","sequence":"additional","affiliation":[{"name":"Seagen Inc, Bothell, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Topletz-Erickson","sequence":"additional","affiliation":[{"name":"Seagen Inc, Bothell, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peigen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Seagen Inc, Bothell, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Seagen Inc, Bothell, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juneko E","family":"Grilley-Olson","sequence":"additional","affiliation":[{"name":"Duke Cancer Institute, Durham, North Carolina, USA"},{"name":"Duke University, Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,6,29]]},"reference":[{"key":"2025100313114034000_11.6.e005584.1","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1080\/14737140.2017.1270208","article-title":"Cancer Immunotherapy: activating innate and adaptive immunity through Cd40 agonists","volume":"17","author":"Beatty","year":"2017","journal-title":"Expert Rev Anticancer Ther"},{"key":"2025100313114034000_11.6.e005584.2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-2064"},{"key":"2025100313114034000_11.6.e005584.3","doi-asserted-by":"crossref","first-page":"3378","DOI":"10.1182\/blood.V85.12.3378.bloodjournal85123378","article-title":"Tumor necrosis factor ligand Superfamily: involvement in the pathology of malignant Lymphomas","volume":"85","author":"Gruss","year":"1995","journal-title":"Blood"},{"key":"2025100313114034000_11.6.e005584.4","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V84.8.2597.2597"},{"key":"2025100313114034000_11.6.e005584.5","doi-asserted-by":"publisher","DOI":"10.1084\/jem.183.1.159"},{"key":"2025100313114034000_11.6.e005584.6","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-5699(98)01340-1"},{"key":"2025100313114034000_11.6.e005584.7","doi-asserted-by":"crossref","first-page":"393","DOI":"10.3109\/10428199709055580","article-title":"Cd40\/Cd40 ligand interactions in normal, reactive and malignant Lympho-hematopoietic tissues","volume":"24","author":"Gruss","year":"1997","journal-title":"Leukemia & Lymphoma"},{"key":"2025100313114034000_11.6.e005584.8","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1182\/blood.V76.12.2449.2449","article-title":"Temporal Association of Cd40 antigen expression with discrete stages of human B-cell Ontogeny and the efficacy of anti-Cd40 Immunotoxins against Clonogenic B-lineage acute Lymphoblastic leukemia as well as B-lineage non-Hodgkin\u2019s lymphoma cells","volume":"76","author":"Uckun","year":"1990","journal-title":"Blood"},{"key":"2025100313114034000_11.6.e005584.9","doi-asserted-by":"crossref","DOI":"10.1158\/1538-7445.AM2015-2472","article-title":"SEA-Cd40, a sugar engineered non-Fucosylated anti-Cd40 antibody with improved immune activating capabilities cancer Res","volume":"75","author":"Gardai","year":"2015","journal-title":"Cancer Res"},{"key":"2025100313114034000_11.6.e005584.10","doi-asserted-by":"crossref","DOI":"10.1200\/jco.2015.33.15_suppl.3074","article-title":"A sugar engineered non-Fucosylated anti-Cd40 antibody, SEA-Cd40, with enhanced immune stimulatory activity alone and in combination with immune Checkpoint inhibitors","volume":"33","author":"Gardai","year":"2015","journal-title":"JCO"},{"key":"2025100313114034000_11.6.e005584.11","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.3109\/10428194.2015.1007504","article-title":"Dacetuzumab plus Rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: a randomized, double-blind, placebo-controlled phase 2B trial","volume":"56","author":"Fayad","year":"2015","journal-title":"Leuk Lymphoma"},{"key":"2025100313114034000_11.6.e005584.12","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2018.1466767"},{"key":"2025100313114034000_11.6.e005584.13","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1146\/annurev-med-062518-045435","article-title":"Cd40 agonist antibodies in cancer Immunotherapy","volume":"71","author":"Vonderheide","year":"2020","journal-title":"Annu Rev Med"},{"key":"2025100313114034000_11.6.e005584.14","doi-asserted-by":"publisher","DOI":"10.1038\/8426"},{"key":"2025100313114034000_11.6.e005584.15","doi-asserted-by":"publisher","DOI":"10.1038\/10503"},{"key":"2025100313114034000_11.6.e005584.16","doi-asserted-by":"publisher","DOI":"10.1038\/10495"},{"key":"2025100313114034000_11.6.e005584.17","doi-asserted-by":"crossref","DOI":"10.1158\/1538-7445.AM2020-5535","article-title":"SEA-Cd40 is a non-Fucosylated anti-Cd40 antibody with potent pharmacodynamic activity in Preclinical models and patients with advanced solid tumors","volume":"80","author":"Neff-LaFord","year":"2020","journal-title":"Cancer Res"},{"key":"2025100313114034000_11.6.e005584.18","doi-asserted-by":"crossref","unstructured":"Zeng W , Neff-LaFord H , Ansari S , et al . synergy between SEA-Cd40 and chemotherapeutics drives curative antitumor activity in Preclinical models. 35th anniversary annual meeting (SITC 2020). 35th Anniversary Annual Meeting (SITC 2020); November 2020 doi:10.1136\/jitc-2020-SITC2020.0438","DOI":"10.1136\/jitc-2020-SITC2020.0438"},{"key":"2025100313114034000_11.6.e005584.19","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2883"},{"key":"2025100313114034000_11.6.e005584.20","doi-asserted-by":"crossref","DOI":"10.1186\/1756-8722-7-44","article-title":"A phase II study of Dacetuzumab (SGN-40) in patients with Relapsed diffuse large B-cell lymphoma (DLBCL) and Correlative analyses of patient-specific factors","volume":"7","author":"de Vos","year":"2014","journal-title":"J Hematol Oncol"},{"key":"2025100313114034000_11.6.e005584.21","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.08.3311"},{"key":"2025100313114034000_11.6.e005584.22","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2009.008003"},{"key":"2025100313114034000_11.6.e005584.23","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30532-5"},{"key":"2025100313114034000_11.6.e005584.24","doi-asserted-by":"publisher","DOI":"10.4161\/mabs.19941"},{"key":"2025100313114034000_11.6.e005584.25","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2022.40.4_suppl.559","article-title":"Preliminary results of a phase 1 study of SEA-Cd40, Gemcitabine, NAB-paclitaxel, and Pembrolizumab in patients with metastatic Pancreatic Ductal adenocarcinoma (PDAC)","volume":"40","author":"Bajor","year":"2022","journal-title":"JCO"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2022-005584","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T20:11:49Z","timestamp":1759522309000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2022-005584"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6]]},"references-count":25,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6,29]]},"published-print":{"date-parts":[[2023,6]]}},"alternative-id":["10.1136\/jitc-2022-005584"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2022-005584","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6]]}}}