{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:21:40Z","timestamp":1790842900931,"version":"4.1.0"},"reference-count":53,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"content-version":"unspecified","delay-in-days":17,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008272","name":"Novartis Pharmaceuticals Corporation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,10,22]]},"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>NIZ985 is a recombinant heterodimer of physiologically active interleukin (IL-)15 and IL-15 receptor alpha. In preclinical models, NIZ985 promotes cytotoxic lymphocyte proliferation, killing function, and organ\/tumor infiltration, with resultant anticancer effects. In this first-in-human study, we assessed the safety, pharmacokinetics, and immune effects of NIZ985 in patients with metastatic or unresectable solid tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Single agent NIZ985 dose escalation data are reported from a phase I dose escalation\/expansion study of NIZ985 as monotherapy. Adult patients (N=14) received 0.25, 0.5, 1, 2 or 4\u2009\u00b5g\/kg subcutaneous NIZ985 three times weekly (TIW) for the first 2 weeks of each 28-day cycle, in an accelerated 3+3\u2009dose escalation trial design. IL-15 and endogenous cytokines were monitored by ELISA and multiplexed electrochemiluminescent assays. Multiparameter flow cytometry assessed the frequency, phenotype and proliferation of peripheral blood mononuclear cells. Preliminary antitumor activity was assessed by overall response rate (Response Evaluation Criteria in Solid Tumors V.1.1).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      As of March 2, 2020, median treatment duration was 7.5 weeks (range 1.1\u201377.1). Thirteen patients had discontinued and one (uveal melanoma) remains on treatment with stable disease. Best clinical response was stable disease (3 of 14 patients; 21%). The most frequent adverse events (AEs) were circular erythematous injection site reactions (100%), chills (71%), fatigue (57%), and fever (50%). Treatment-related grade 3\/4 AEs occurred in six participants (43%); treatment-related serious AEs (SAEs) in three (21%). The per-protocol maximum tolerated dose was not reached. Pharmacokinetic accumulation of serum IL-15 in the first week was followed by significantly lower levels in week 2, likely due to more rapid cytokine consumption by an expanding lymphocyte pool. NIZ985 treatment was associated with increases in several cytokines, including interferon (IFN)-\u03b3, IL-18, C-X-C motif chemokine ligand 10, and tumor necrosis factor-\u03b2, plus significant induction of cytotoxic lymphocyte proliferation (including natural killer and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells), increased CD16\n                      <jats:sup>+<\/jats:sup>\n                      monocytes, and increased CD163\n                      <jats:sup>+<\/jats:sup>\n                      macrophages at injection sites.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Subcutaneous NIZ985 TIW was generally well tolerated in patients with advanced cancer and produced immune activation paralleling preclinical observations, with induction of IFN-\u03b3 and proliferation of cytotoxic lymphocytes. Due to delayed SAEs at the two highest dose levels, administration is being changed to once-weekly in a revised protocol, as monotherapy and combined with checkpoint inhibitor spartalizumab. These alterations are expected to maximize the potential of NIZ985 as a novel immunotherapy.<\/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=\"NCT02452268\">NCT02452268<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2021-003388","type":"journal-article","created":{"date-parts":[[2021,11,19]],"date-time":"2021-11-19T10:36:41Z","timestamp":1637318201000},"page":"e003388","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["Phase I study of single agent NIZ985, a recombinant heterodimeric IL-15 agonist, in adult patients with metastatic or unresectable solid tumors"],"prefix":"10.1136","volume":"9","clinical-trial-number":[{"clinical-trial-number":"nct02452268","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04261439","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03388632","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03905135","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03759184","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02689453","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4118-7524","authenticated-orcid":false,"given":"Kevin","family":"Conlon","sequence":"first","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9146-5641","authenticated-orcid":false,"given":"Dionysios C","family":"Watson","sequence":"additional","affiliation":[{"name":"Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA"},{"name":"University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4500-6660","authenticated-orcid":false,"given":"Thomas A","family":"Waldmann","sequence":"additional","affiliation":[{"name":"Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0745-7922","authenticated-orcid":false,"given":"Antonio","family":"Valentin","sequence":"additional","affiliation":[{"name":"Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1030-2662","authenticated-orcid":false,"given":"Cristina","family":"Bergamaschi","sequence":"additional","affiliation":[{"name":"Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8925-8128","authenticated-orcid":false,"given":"Barbara K","family":"Felber","sequence":"additional","affiliation":[{"name":"Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9395-3473","authenticated-orcid":false,"given":"Cody J","family":"Peer","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Program, Center for Cancer Research, NCI, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2428-5613","authenticated-orcid":false,"given":"William D","family":"Figg","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Program, Center for Cancer Research, NCI, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4339-9800","authenticated-orcid":false,"given":"E Lake","family":"Potter","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, NIAID, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7448-7040","authenticated-orcid":false,"given":"Mario","family":"Roederer","sequence":"additional","affiliation":[{"name":"Vaccine Research Center, NIAID, Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1471-6723","authenticated-orcid":false,"given":"Douglas G","family":"McNeel","sequence":"additional","affiliation":[{"name":"Carbone Cancer Center, University of Wisconsin Madison, Madison, Wisconsin, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0872-7306","authenticated-orcid":false,"given":"John A","family":"Thompson","sequence":"additional","affiliation":[{"name":"Seattle Cancer Care Alliance, Seattle, Washington, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6271-0831","authenticated-orcid":false,"given":"Sumati","family":"Gupta","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0788-7938","authenticated-orcid":false,"given":"Rom","family":"Leidner","sequence":"additional","affiliation":[{"name":"Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0458-7614","authenticated-orcid":false,"given":"Andrea","family":"Wang-Gillam","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Medicine, Washington University in Saint Louis, St Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4746-1168","authenticated-orcid":false,"given":"Nehal S","family":"Parikh","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4882-049X","authenticated-orcid":false,"given":"Debby","family":"Long","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2842-9437","authenticated-orcid":false,"given":"Sema","family":"Kurtulus","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9684-160X","authenticated-orcid":false,"given":"Lang","family":"Ho Lee","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0427-0879","authenticated-orcid":false,"given":"Niladri Roy","family":"Chowdhury","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7407-5847","authenticated-orcid":false,"given":"Florent","family":"Bender","sequence":"additional","affiliation":[{"name":"Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4027-4036","authenticated-orcid":false,"given":"George N","family":"Pavlakis","sequence":"additional","affiliation":[{"name":"Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,11,19]]},"reference":[{"key":"2025100301513123000_9.11.e003388.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.24.021605.090727"},{"key":"2025100301513123000_9.11.e003388.2","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-15-0009"},{"key":"2025100301513123000_9.11.e003388.3","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-06-2399"},{"key":"2025100301513123000_9.11.e003388.4","doi-asserted-by":"publisher","DOI":"10.2337\/db12-0049"},{"key":"2025100301513123000_9.11.e003388.5","first-page":"212","article-title":"The toxicity and benefit of various dosing strategies for interleukin-2 in metastatic melanoma and renal cell carcinoma","volume":"6","author":"Pachella","year":"2015","journal-title":"J Adv Pract Oncol"},{"key":"2025100301513123000_9.11.e003388.6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.200363097"},{"key":"2025100301513123000_9.11.e003388.7","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.1107778"},{"key":"2025100301513123000_9.11.e003388.8","doi-asserted-by":"crossref","DOI":"10.3390\/cancers13040837","article-title":"Heterodimeric IL-15 in cancer immunotherapy","volume":"13","author":"Bergamaschi","year":"2021","journal-title":"Cancers"},{"key":"2025100301513123000_9.11.e003388.9","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041389"},{"key":"2025100301513123000_9.11.e003388.10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.11.6537"},{"key":"2025100301513123000_9.11.e003388.11","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-08-2814"},{"key":"2025100301513123000_9.11.e003388.12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.50.29862"},{"key":"2025100301513123000_9.11.e003388.13","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705725200"},{"key":"2025100301513123000_9.11.e003388.14","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900693"},{"key":"2025100301513123000_9.11.e003388.15","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20071913"},{"key":"2025100301513123000_9.11.e003388.16","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(02)00429-6"},{"key":"2025100301513123000_9.11.e003388.17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.461756"},{"key":"2025100301513123000_9.11.e003388.18","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-10-384362"},{"key":"2025100301513123000_9.11.e003388.19","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2014.84"},{"key":"2025100301513123000_9.11.e003388.20","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.cyto.2018.01.011","article-title":"Optimized administration of hetIL-15 expands lymphocytes and minimizes toxicity in rhesus macaques","volume":"108","author":"Bergamaschi","year":"2018","journal-title":"Cytokine"},{"key":"2025100301513123000_9.11.e003388.21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006902"},{"key":"2025100301513123000_9.11.e003388.22","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.4.2099"},{"key":"2025100301513123000_9.11.e003388.23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0600240103"},{"key":"2025100301513123000_9.11.e003388.24","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.9.6072"},{"key":"2025100301513123000_9.11.e003388.25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307298101"},{"key":"2025100301513123000_9.11.e003388.26","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-1808"},{"key":"2025100301513123000_9.11.e003388.27","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-000599"},{"key":"2025100301513123000_9.11.e003388.28","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-0045"},{"key":"2025100301513123000_9.11.e003388.29","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7470"},{"key":"2025100301513123000_9.11.e003388.30","doi-asserted-by":"publisher","DOI":"10.1006\/cimm.1995.1216"},{"key":"2025100301513123000_9.11.e003388.31","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1419"},{"key":"2025100301513123000_9.11.e003388.32","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102604"},{"key":"2025100301513123000_9.11.e003388.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0902637106"},{"key":"2025100301513123000_9.11.e003388.34","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1200\/JCO.2014.57.3329","article-title":"Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer","volume":"33","author":"Conlon","year":"2015","journal-title":"J Clin Oncol"},{"key":"2025100301513123000_9.11.e003388.35","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018028332"},{"key":"2025100301513123000_9.11.e003388.36","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-2451"},{"key":"2025100301513123000_9.11.e003388.37","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-3468"},{"key":"2025100301513123000_9.11.e003388.38","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-0945"},{"key":"2025100301513123000_9.11.e003388.39","doi-asserted-by":"crossref","first-page":"2515","DOI":"10.1182\/blood-2017-12-823757","article-title":"First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation","volume":"131","author":"Romee","year":"2018","journal-title":"Blood"},{"key":"2025100301513123000_9.11.e003388.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2016.08.009"},{"key":"2025100301513123000_9.11.e003388.41","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-15-0123"},{"key":"2025100301513123000_9.11.e003388.42","doi-asserted-by":"crossref","DOI":"10.1136\/bcr-2020-237008","article-title":"IgA nephropathy after pembrolizumab therapy for mesothelioma","volume":"13","author":"Wang","year":"2020","journal-title":"BMJ Case Rep"},{"key":"2025100301513123000_9.11.e003388.43","doi-asserted-by":"crossref","DOI":"10.1097\/MD.0000000000020464","article-title":"Nivolumab-induced IgA nephropathy in a patient with advanced gastric cancer: a case report","volume":"99","author":"Tanabe","year":"2020","journal-title":"Medicine"},{"key":"2025100301513123000_9.11.e003388.44","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050732"},{"key":"2025100301513123000_9.11.e003388.45","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1009278","article-title":"Interleukin-15 response signature predicts RhCMV\/SIV vaccine efficacy","volume":"17","author":"Barren\u00e4s","year":"2021","journal-title":"PLoS Pathog"},{"key":"2025100301513123000_9.11.e003388.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2017.08.010"},{"key":"2025100301513123000_9.11.e003388.47","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1080\/14712598.2020.1738379","article-title":"Rationale for IL-15 superagonists in cancer immunotherapy","volume":"20","author":"Knudson","year":"2020","journal-title":"Expert Opin Biol Ther"},{"key":"2025100301513123000_9.11.e003388.48","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20191062","article-title":"Interleukin-15 (dys)regulation of lymphoid homeostasis: Implications for therapy of autoimmunity and cancer","volume":"217","author":"Waldmann","year":"2020","journal-title":"J Exp Med"},{"key":"2025100301513123000_9.11.e003388.49","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2020.00868","article-title":"Il-15 in the combination immunotherapy of cancer","volume":"11","author":"Waldmann","year":"2020","journal-title":"Front Immunol"},{"key":"2025100301513123000_9.11.e003388.50","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1089\/jir.2017.0101","article-title":"Il-2 and beyond in cancer immunotherapy","volume":"38","author":"Wrangle","year":"2018","journal-title":"J Interferon Cytokine Res"},{"key":"2025100301513123000_9.11.e003388.51","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(18)30148-7"},{"key":"2025100301513123000_9.11.e003388.52","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2018029371"},{"key":"2025100301513123000_9.11.e003388.53","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-2710"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2021-003388","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T08:51:42Z","timestamp":1759481502000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2021-003388"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11]]},"references-count":53,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11,19]]},"published-print":{"date-parts":[[2021,11]]}},"alternative-id":["10.1136\/jitc-2021-003388"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2021-003388","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11]]}}}