{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:27:33Z","timestamp":1792459653008,"version":"4.5.0"},"reference-count":60,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T00:00:00Z","timestamp":1613088000000},"content-version":"unspecified","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2020,12,22]]},"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:p>\n                  <jats:bold>Background<\/jats:bold> Human cancers are extraordinarily heterogeneous in terms of tumor antigen expression, immune infiltration and composition. A common feature, however, is the host\u2032s inability to mount potent immune responses that prevent tumor growth effectively. Often, naturally primed CD8<jats:sup>+<\/jats:sup> T cells against solid tumors lack adequate stimulation and efficient tumor tissue penetration due to an immune hostile tumor microenvironment.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Methods<\/jats:bold> To address these shortcomings, we cloned tumor-associated antigens (TAA) and the immune-stimulatory ligand 4-1BBL into the genome of modified vaccinia Ankara (MVA) for intratumoral virotherapy.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Results<\/jats:bold> Local treatment with MVA-TAA-4-1BBL resulted in control of established tumors. Intratumoral injection of MVA localized mainly to the tumor with minimal leakage to the tumor-draining lymph node. In situ infection by MVA-TAA-4-1BBL triggered profound changes in the tumor microenvironment, including the induction of multiple proinflammatory molecules and immunogenic cell death. These changes led to the reactivation and expansion of antigen-experienced, tumor-specific cytotoxic CD8<jats:sup>+<\/jats:sup> T cells that were essential for the therapeutic antitumor effect. Strikingly, we report the induction of a systemic antitumor immune response including tumor antigen spread by local MVA-TAA-4-1BBL treatment which controlled tumor growth at distant, untreated lesions and protected against local and systemic tumor rechallenge. In all cases, 4-1BBL adjuvanted MVA was superior to MVA.<\/jats:p>\n               <jats:p>\n                  <jats:bold>Conclusion<\/jats:bold> Intratumoral 4-1BBL-armed MVA immunotherapy induced a profound reactivation and expansion of potent tumor-specific CD8<jats:sup>+<\/jats:sup> T cells as well as favorable proinflammatory changes in the tumor microenvironment, leading to elimination of tumors and protective immunological memory.<\/jats:p>","DOI":"10.1136\/jitc-2020-001586","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T11:55:59Z","timestamp":1613130959000},"page":"e001586","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":24,"title":["Intratumoral virotherapy with 4-1BBL armed modified vaccinia Ankara eradicates solid tumors and promotes protective immune memory"],"prefix":"10.1136","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2672-9134","authenticated-orcid":false,"given":"Maria","family":"Hinterberger","sequence":"first","affiliation":[{"name":"Bavarian Nordic GmbH, Planegg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raphael","family":"Giessel","sequence":"additional","affiliation":[{"name":"Bavarian Nordic GmbH, Planegg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Fiore","sequence":"additional","affiliation":[{"name":"Bavarian Nordic GmbH, Planegg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabienne","family":"Graebnitz","sequence":"additional","affiliation":[{"name":"Bavarian Nordic GmbH, Planegg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Bathke","sequence":"additional","affiliation":[{"name":"Bavarian Nordic GmbH, Planegg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Wennier","sequence":"additional","affiliation":[{"name":"Bavarian Nordic GmbH, Planegg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Chaplin","sequence":"additional","affiliation":[{"name":"Bavarian Nordic GmbH, Planegg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1360-348X","authenticated-orcid":false,"given":"Ignacio","family":"Melero","sequence":"additional","affiliation":[{"name":"Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain"},{"name":"IdiSNA, Navarra Institute for Health Research, Pamplona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), Pamplona, Spain"},{"name":"Department of Oncology, Cl\u00ednica Universidad de Navarra, Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Suter","sequence":"additional","affiliation":[{"name":"Bavarian Nordic GmbH, Planegg, Germany"},{"name":"Vetsuisse Fakult\u00e4t, Dekanat, Bereich Immunologie, Universit\u00e4t Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henning","family":"Lauterbach","sequence":"additional","affiliation":[{"name":"Bavarian Nordic GmbH, Planegg, Germany"},{"name":"Present address: Hookipa Pharma Inc, 350 Fifth Avenue, Room\/Suite 7240, New York City, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7410-1865","authenticated-orcid":false,"given":"Pedro","family":"Berraondo","sequence":"additional","affiliation":[{"name":"Program of Immunology and Immunotherapy, Cima Universidad de Navarra, Pamplona, Spain"},{"name":"IdiSNA, Navarra Institute for Health Research, Pamplona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubertus","family":"Hochrein","sequence":"additional","affiliation":[{"name":"Bavarian Nordic GmbH, Planegg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Medina-Echeverz","sequence":"additional","affiliation":[{"name":"Bavarian Nordic GmbH, Planegg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,2,12]]},"reference":[{"key":"2025100305233095000_9.2.e001586.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3239"},{"key":"2025100305233095000_9.2.e001586.2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00262-016-1909-3","article-title":"Tumor-Directed immunotherapy can generate tumor-specific T cell responses through localized co-stimulation","volume":"66","author":"Ellmark","year":"2017","journal-title":"Cancer Immunol Immunother"},{"key":"2025100305233095000_9.2.e001586.3","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601145"},{"key":"2025100305233095000_9.2.e001586.4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.58.3377"},{"key":"2025100305233095000_9.2.e001586.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-018-0014-6"},{"key":"2025100305233095000_9.2.e001586.6","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2019.1596006"},{"key":"2025100305233095000_9.2.e001586.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.03.011"},{"key":"2025100305233095000_9.2.e001586.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1817307"},{"key":"2025100305233095000_9.2.e001586.9","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1093\/infdis\/jiz070","article-title":"Safety and immunogenicity of a 2-Dose heterologous vaccination regimen with Ad26.ZEBOV and MVA-BN-Filo Ebola vaccines: 12-month data from a phase 1 randomized clinical trial in Uganda and Tanzania","volume":"220","author":"Anywaine","year":"2019","journal-title":"J Infect Dis"},{"key":"2025100305233095000_9.2.e001586.10","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-0183"},{"key":"2025100305233095000_9.2.e001586.11","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01617-08"},{"key":"2025100305233095000_9.2.e001586.12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI33940"},{"key":"2025100305233095000_9.2.e001586.13","article-title":"Broad antibody and cellular immune response from a phase 2 clinical trial with a novel multivalent poxvirus based RSV vaccine","author":"Jordan","year":"2020","journal-title":"J Infect Dis"},{"key":"2025100305233095000_9.2.e001586.14","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1177\/135965350501000212","article-title":"Therapeutic vaccination of HIV-1-infected patients on HAART with a recombinant HIV-1 nef-expressing MVA: safety, immunogenicity and influence on viral load during treatment interruption","volume":"10","author":"Harrer","year":"2005","journal-title":"Antivir Ther"},{"key":"2025100305233095000_9.2.e001586.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2009.05.095"},{"key":"2025100305233095000_9.2.e001586.16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0195897"},{"key":"2025100305233095000_9.2.e001586.17","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2013.00251","article-title":"Genetic Adjuvantation of recombinant MVA with CD40L potentiates CD8 T cell mediated immunity","volume":"4","author":"Lauterbach","year":"2013","journal-title":"Front Immunol"},{"key":"2025100305233095000_9.2.e001586.18","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-019-12998-6","article-title":"Synergistic cancer immunotherapy combines MVA-CD40L induced innate and adaptive immunity with tumor targeting antibodies","volume":"10","author":"Medina-Echeverz","year":"2019","journal-title":"Nat Commun"},{"key":"2025100305233095000_9.2.e001586.19","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2009.00765.x"},{"key":"2025100305233095000_9.2.e001586.20","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-11-0314"},{"key":"2025100305233095000_9.2.e001586.21","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2015.00117"},{"key":"2025100305233095000_9.2.e001586.22","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-1272"},{"key":"2025100305233095000_9.2.e001586.23","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aav5989","article-title":"Tumor-Targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy","volume":"11","author":"Claus","year":"2019","journal-title":"Sci Transl Med"},{"key":"2025100305233095000_9.2.e001586.24","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-3654"},{"key":"2025100305233095000_9.2.e001586.25","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aax7992","article-title":"Intratumoral expression of IL-7 and IL-12 using an oncolytic virus increases systemic sensitivity to immune checkpoint blockade","volume":"12","author":"Nakao","year":"2020","journal-title":"Sci Transl Med"},{"key":"2025100305233095000_9.2.e001586.26","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.aal1713","article-title":"Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via sting and Batf3-dependent dendritic cells","volume":"2","author":"Dai","year":"2017","journal-title":"Sci Immunol"},{"key":"2025100305233095000_9.2.e001586.27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.18.9730"},{"key":"2025100305233095000_9.2.e001586.28","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-1620"},{"key":"2025100305233095000_9.2.e001586.29","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-019-10088-1","article-title":"Optimization of 4-1BB antibody for cancer immunotherapy by balancing agonistic strength with Fc\u03b3R affinity","volume":"10","author":"Qi","year":"2019","journal-title":"Nat Commun"},{"key":"2025100305233095000_9.2.e001586.30","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-1847"},{"key":"2025100305233095000_9.2.e001586.31","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-02-408179"},{"key":"2025100305233095000_9.2.e001586.32","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0565-5"},{"key":"2025100305233095000_9.2.e001586.33","doi-asserted-by":"publisher","DOI":"10.1038\/ni1009"},{"key":"2025100305233095000_9.2.e001586.34","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.27"},{"key":"2025100305233095000_9.2.e001586.35","doi-asserted-by":"publisher","DOI":"10.4161\/onci.26889"},{"key":"2025100305233095000_9.2.e001586.36","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy413"},{"key":"2025100305233095000_9.2.e001586.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13035-2"},{"key":"2025100305233095000_9.2.e001586.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2008.01.052"},{"key":"2025100305233095000_9.2.e001586.39","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2010.121"},{"key":"2025100305233095000_9.2.e001586.40","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0009659","article-title":"Immune requirements of post-exposure immunization with modified vaccinia Ankara of lethally infected mice","volume":"5","author":"Lauterbach","year":"2010","journal-title":"PLoS One"},{"key":"2025100305233095000_9.2.e001586.41","doi-asserted-by":"publisher","DOI":"10.1172\/JCI73639"},{"key":"2025100305233095000_9.2.e001586.42","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2019-000325"},{"key":"2025100305233095000_9.2.e001586.43","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-1056"},{"key":"2025100305233095000_9.2.e001586.44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1118834109"},{"key":"2025100305233095000_9.2.e001586.45","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20121172"},{"key":"2025100305233095000_9.2.e001586.46","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-0045"},{"key":"2025100305233095000_9.2.e001586.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.07.025"},{"key":"2025100305233095000_9.2.e001586.48","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1038\/s41590-019-0342-0","article-title":"Lymph node conduits transport virions for rapid T cell activation","volume":"20","author":"Reynoso","year":"2019","journal-title":"Nat Immunol"},{"key":"2025100305233095000_9.2.e001586.49","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-13-0067"},{"key":"2025100305233095000_9.2.e001586.50","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1146\/annurev-immunol-100919-023531","article-title":"Vitiligo: mechanisms of pathogenesis and treatment","volume":"38","author":"Frisoli","year":"2020","journal-title":"Annu Rev Immunol"},{"key":"2025100305233095000_9.2.e001586.51","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201445388"},{"key":"2025100305233095000_9.2.e001586.52","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms16073"},{"key":"2025100305233095000_9.2.e001586.53","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15221"},{"key":"2025100305233095000_9.2.e001586.54","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0812-9"},{"key":"2025100305233095000_9.2.e001586.55","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400003"},{"key":"2025100305233095000_9.2.e001586.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.01.015"},{"key":"2025100305233095000_9.2.e001586.57","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2016.124"},{"key":"2025100305233095000_9.2.e001586.58","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12657"},{"key":"2025100305233095000_9.2.e001586.59","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.8.4911-4927.2003"},{"key":"2025100305233095000_9.2.e001586.60","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.1.63"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2020-001586","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T12:23:41Z","timestamp":1759494221000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2020-001586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2]]},"references-count":60,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2,12]]},"published-print":{"date-parts":[[2021,2]]}},"alternative-id":["10.1136\/jitc-2020-001586"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2020-001586","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2]]}}}