{"doi":"10.1136/jitc-2021-003532","title":"Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies","abstract":"<jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>On the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved chimeric antigen receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and costimulation of T cells will facilitate clinical development of CD137 agonists in the clinic.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>We used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored on treatment with agonist anti-CD137 monoclonal antibodies (mAbs). Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 mAb (Urelumab). Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISA and Luminex. Flow cytometry was used to monitor CD137 surface expression.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>CD137 costimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 costimulation inside subcutaneously implanted Matrigel plugs. The CD137 signaling domain-containing CAR T cells readily released sCD137 and acquired CD137 surface expression on antigen recognition. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion</jats:title>\n                  <jats:p>sCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents.</jats:p>\n               </jats:sec>","journal":"Journal for ImmunoTherapy of Cancer","year":2022,"id":682952,"datarank":0.4943755299006494,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.0,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1784139,"name":"Arantza Azpilikueta","orcid":null,"position":1,"is_corresponding":false},{"id":1784140,"name":"Irene Olivera","orcid":null,"position":2,"is_corresponding":false},{"id":1784141,"name":"Assunta Cirella","orcid":null,"position":3,"is_corresponding":false},{"id":632515,"name":"Álvaro Teijeira","orcid":"0000-0002-7339-4464","position":4,"is_corresponding":false},{"id":1683383,"name":"Maria C Ochoa","orcid":null,"position":5,"is_corresponding":false},{"id":421723,"name":"Maite Álvarez","orcid":"0000-0002-5969-9181","position":6,"is_corresponding":false},{"id":1784142,"name":"Iñaki Eguren-Santamaria","orcid":"0000-0003-1581-3728","position":7,"is_corresponding":false},{"id":1784143,"name":"Carlos Luri-Rey","orcid":null,"position":8,"is_corresponding":false},{"id":1784144,"name":"Maria E Rodriguez-Ruiz","orcid":null,"position":9,"is_corresponding":false},{"id":1283653,"name":"Xinxin Nie","orcid":null,"position":10,"is_corresponding":false},{"id":59437,"name":"Lieping Chen","orcid":"0000-0002-6825-3069","position":11,"is_corresponding":false},{"id":1784145,"name":"Sonia Guedan","orcid":null,"position":12,"is_corresponding":false},{"id":1784146,"name":"Miguel F Sanmamed","orcid":null,"position":13,"is_corresponding":false},{"id":1364475,"name":"Jose Luis Perez Gracia","orcid":null,"position":14,"is_corresponding":false},{"id":1183409,"name":"Ignacio Melero","orcid":"0000-0002-1360-348X","position":15,"is_corresponding":false},{"id":1784138,"name":"Javier Glez-Vaz","orcid":"0000-0001-8936-190X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies","abstract":"<jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>On the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved chimeric antigen receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and costimulation of T cells will facilitate clinical development of CD137 agonists in the clinic.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>We used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored on treatment with agonist anti-CD137 monoclonal antibodies (mAbs). Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 mAb (Urelumab). Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISA and Luminex. Flow cytometry was used to monitor CD137 surface expression.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>CD137 costimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 costimulation inside subcutaneously implanted Matrigel plugs. The CD137 signaling domain-containing CAR T cells readily released sCD137 and acquired CD137 surface expression on antigen recognition. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion</jats:title>\n                  <jats:p>sCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents.</jats:p>\n               </jats:sec>","is_dataset_classified":null,"base_score":3.295836866004329,"endowment":3.295836866004329,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"35236742","pmcid":"PMC8896037","openalex_id":"https://openalex.org/W4214833888","authors":[],"funders":[{"funder_name":"MINECO","grant_id":"PID2020-112892RB-100","title":null},{"funder_name":"MINECO","grant_id":"SAF2017-83267-C2-1-R","title":null},{"funder_name":"European Union","grant_id":"635122","title":"Professional cross-priming for ovary and prostate cancer"},{"funder_name":"Fundación La Caixa","grant_id":"","title":null},{"funder_name":"FEDER","grant_id":"","title":null},{"funder_name":"Fundación BBVA","grant_id":"","title":null},{"funder_name":"AECC","grant_id":"","title":null}],"total_grants":7,"fwci":1.8577,"citation_percentile":0.8766013,"influential_citations":0,"citation_trend":[{"year":2022,"count":1},{"year":2023,"count":7},{"year":2024,"count":4},{"year":2025,"count":8},{"year":2026,"count":6}],"oa_status":"gold","license":"cc-by-nc","oa_locations":[{"url":"https://jitc.bmj.com/content/jitc/10/3/e003532.full.pdf","host_type":"journal"},{"url":"https://jitc.bmj.com/content/jitc/10/3/e003532.full.pdf","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1136/jitc-2021-003532","host_type":"publisher"},{"url":"https://doi.org/10.1136/jitc-2021-003532","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/35236742","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8896037","host_type":"repository"},{"url":"https://hdl.handle.net/2445/208387","host_type":"repository"},{"url":"https://doaj.org/article/73397a239a8744e29c59d4accc19c284","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC8896037","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8896037?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1136/jitc-2021-003532","host_type":""},{"url":"https://hdl.handle.net/10171/117216","host_type":""}],"fields_of_study":["Cancer Immunotherapy and Biomarkers","CAR-T cell therapy research","T-cell and B-cell Immunology","0301 basic medicine","03 medical and health sciences","Animals","Biomarkers","CD8-Positive T-Lymphocytes","Humans","Immunotherapy","Mice","Neoplasms","Receptors, Tumor Necrosis Factor"],"mesh_terms":["Animals","Humans","Immunotherapy","Neoplasms","Biomarkers","Receptors, Tumor Necrosis Factor","CD8-Positive T-Lymphocytes","Mice"],"keywords":["CD137","Agonist","CD8","Chemistry","Cancer research","Monoclonal antibody","Immunotherapy","Molecular biology","Antigen","Antibody","Receptor","Immunology","Medicine","Biology","Immune system","Biochemistry","Receptors","Tumor","Immunologic","Biomarkers","Costimulatory And Inhibitory T-cell Receptors","Ratolins (Animals de laboratori)","Immunoteràpia","Neoplasms. Tumors. Oncology. Including cancer and carcinogens","CD8-Positive T-Lymphocytes","Receptors, Tumor Necrosis Factor","Mice","Neoplasms","Immunotherapy Biomarkers","Animals","Humans","RC254-282"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"},{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T21:48:19.574947Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}