{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T23:53:11Z","timestamp":1793145191229,"version":"4.5.0"},"reference-count":48,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T00:00:00Z","timestamp":1617148800000},"content-version":"unspecified","delay-in-days":30,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000645","name":"Jesus College, University of Oxford","doi-asserted-by":"publisher","award":["Doctoral studentship"],"award-info":[{"award-number":["Doctoral studentship"]}],"id":[{"id":"10.13039\/501100000645","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010349","name":"Linacre College, University of Oxford","doi-asserted-by":"publisher","award":["Sir Paul Nurse Junior Research Fellowship"],"award-info":[{"award-number":["Sir Paul Nurse Junior Research Fellowship"]}],"id":[{"id":"10.13039\/100010349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/N013468\/1"],"award-info":[{"award-number":["MR\/N013468\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C5255\/A20936"],"award-info":[{"award-number":["C5255\/A20936"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C552\/A29106"],"award-info":[{"award-number":["C552\/A29106"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C557\/A17720"],"award-info":[{"award-number":["C557\/A17720"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013790","name":"Brain Research UK","doi-asserted-by":"publisher","award":["STU1617-02"],"award-info":[{"award-number":["STU1617-02"]}],"id":[{"id":"10.13039\/100013790","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2021,3,10]]},"published-print":{"date-parts":[[2021,3]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Programmed death-ligand 1 (PD-L1) is an important immune checkpoint protein that can be regarded as a pan-cancer antigen expressed by multiple different cell types within the tumor. While antagonizing PD-L1 is well known to relieve PD-1\/PD-L1-mediated T cell suppression, here we have combined this approach with an immunotherapy strategy to target T cell cytotoxicity directly toward PD-L1-expressing cells. We developed a bi-specific T cell engager (BiTE) crosslinking PD-L1 and CD3\u03b5 and demonstrated targeted cytotoxicity using a clinically relevant patient-derived ascites model. This approach represents an immunological \u2018volte-face\u2019 whereby a tumor immunological defense mechanism can be instantly transformed into an Achilles\u2019 heel for targeted immunotherapy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>The PD-L1 targeting BiTE comprises an anti-PD-L1 single-chain variable fragment (scFv) or nanobody (NB) domain and an anti-CD3 scFv domain in a tandem repeat. The ability to activate T cell cytotoxicity toward PD-L1-expressing cells was established using human carcinoma cells and PD-L1-expressing human (\u2018M2\u2019) macrophages in the presence of autologous T cells. Furthermore, we armed oncolytic herpes simplex virus-1 (oHSV-1) with PD-L1 BiTE and demonstrated successful delivery and targeted cytotoxicity in unpurified cultures of malignant ascites derived from different cancer patients.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>PD-L1 BiTE crosslinks PD-L1-positive cells and CD3\u03b5 on T cells in a \u2018pseudo-synapse\u2019 and triggers T cell activation and release of proinflammatory cytokines such as interferon-gamma (IFN-\u03b3), interferon gamma-induced protein 10 (IP-10) and tumour necrosis factor-\u03b1 (TNF-\u03b1). Activation of endogenous T cells within ascites samples led to significant lysis of tumor cells and M2-like macrophages (CD11b+CD64+ and CD206+\/CD163+). The survival of CD3+ T cells (which can also express PD-L1) was unaffected. Intriguingly, ascites fluid that appeared particularly immunosuppressive led to higher expression of PD-L1 on tumor cells, resulting in improved BiTE-mediated T cell activation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The study reveals that PD-L1 BiTE is an effective immunotherapeutic approach to kill PD-L1-positive tumor cells and macrophages while leaving T cells unharmed. This approach activates endogenous T cells within malignant ascites, generates a proinflammatory response and eliminates cells promoting tumor progression. Using an oncolytic virus for local expression of PD-L1 BiTE also prevents \u2018on-target off-tumor\u2019 systemic toxicities and harnesses immunosuppressive protumor conditions to augment immunotherapy in immunologically \u2018cold\u2019 clinical cancers.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2020-001292","type":"journal-article","created":{"date-parts":[[2021,4,5]],"date-time":"2021-04-05T11:31:28Z","timestamp":1617622288000},"page":"e001292","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":58,"title":["Oncolytic herpesvirus expressing PD-L1 BiTE for cancer therapy: exploiting tumor immune suppression as an opportunity for targeted immunotherapy"],"prefix":"10.1136","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2358-3275","authenticated-orcid":false,"given":"Hena","family":"Khalique","sequence":"first","affiliation":[{"name":"Department of Oncology, University of Oxford, Oxford, Oxfordshire, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Baugh","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Oxford, Oxford, Oxfordshire, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1436-1734","authenticated-orcid":false,"given":"Arthur","family":"Dyer","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Oxford, Oxford, Oxfordshire, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor M.","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Oxford, Oxford, Oxfordshire, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0218-9949","authenticated-orcid":false,"given":"Sally","family":"Frost","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Oxford, Oxford, Oxfordshire, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2360-9786","authenticated-orcid":false,"given":"Sarah","family":"Larkin","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Oxford, Oxford, Oxfordshire, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Lei-Rossmann","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Oxford, Oxford, Oxfordshire, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard W.","family":"Seymour","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Oxford, Oxford, Oxfordshire, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2021,4,5]]},"reference":[{"key":"2025100308135275000_9.4.e001292.1","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1080\/14712598.2020.1729351","article-title":"Combination therapy with oncolytic viruses and immune checkpoint inhibitors","volume":"20","author":"Chiu","year":"2020","journal-title":"Expert Opin Biol Ther"},{"key":"2025100308135275000_9.4.e001292.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0019-2"},{"key":"2025100308135275000_9.4.e001292.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-cancerbio-030617-050254"},{"key":"2025100308135275000_9.4.e001292.4","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/bjc.2015.481","article-title":"Oncolytic viruses: finally delivering","volume":"114","author":"Seymour","year":"2016","journal-title":"Br J Cancer"},{"key":"2025100308135275000_9.4.e001292.5","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-016-1453-9"},{"key":"2025100308135275000_9.4.e001292.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-019-0029-0"},{"key":"2025100308135275000_9.4.e001292.7","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201707567"},{"key":"2025100308135275000_9.4.e001292.8","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-018-0484-x"},{"key":"2025100308135275000_9.4.e001292.9","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-1750"},{"key":"2025100308135275000_9.4.e001292.10","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2014.93"},{"key":"2025100308135275000_9.4.e001292.11","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-0612"},{"key":"2025100308135275000_9.4.e001292.12","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0505-4"},{"key":"2025100308135275000_9.4.e001292.13","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/mt.2013.240","article-title":"T-cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy","volume":"22","author":"Yu","year":"2014","journal-title":"Mol Ther"},{"key":"2025100308135275000_9.4.e001292.14","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-1708"},{"key":"2025100308135275000_9.4.e001292.15","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3389\/fcell.2018.00038","article-title":"Targeting tumor-associated macrophages as a potential strategy to enhance the response to immune checkpoint inhibitors","volume":"6","author":"Cassetta","year":"2018","journal-title":"Front Cell Dev Biol"},{"key":"2025100308135275000_9.4.e001292.16","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/s41419-018-0458-4","article-title":"Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma","volume":"9","author":"Cheng","year":"2018","journal-title":"Cell Death Dis"},{"key":"2025100308135275000_9.4.e001292.17","doi-asserted-by":"crossref","unstructured":"Gershkovitz M , Olga Yajuk TF-L . The PD-L1\/PD-1 axis blocks neutrophil cytotoxicity in cancer. bioRxiv 2020.doi:10.1101\/2020.02.28.969410","DOI":"10.1101\/2020.02.28.969410"},{"key":"2025100308135275000_9.4.e001292.18","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.197194"},{"key":"2025100308135275000_9.4.e001292.19","doi-asserted-by":"publisher","DOI":"10.1186\/1756-8722-6-74"},{"key":"2025100308135275000_9.4.e001292.20","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.07-1606"},{"key":"2025100308135275000_9.4.e001292.21","doi-asserted-by":"publisher","DOI":"10.1038\/nm0995-938"},{"key":"2025100308135275000_9.4.e001292.22","doi-asserted-by":"crossref","first-page":"17004","DOI":"10.1038\/celldisc.2017.4","article-title":"Structural basis of a novel PD-L1 nanobody for immune checkpoint blockade","volume":"3","author":"Zhang","year":"2017","journal-title":"Cell Discov"},{"key":"2025100308135275000_9.4.e001292.23","doi-asserted-by":"crossref","first-page":"57964","DOI":"10.18632\/oncotarget.19865","article-title":"CD3xPDL1 bi-specific T cell engager (BiTE) simultaneously activates T cells and NKT cells, kills PDL1+ tumor cells, and extends the survival of tumor-bearing humanized mice","volume":"8","author":"Horn","year":"2017","journal-title":"Oncotarget"},{"key":"2025100308135275000_9.4.e001292.24","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3302717"},{"key":"2025100308135275000_9.4.e001292.25","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-0428-0_2"},{"key":"2025100308135275000_9.4.e001292.26","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/978-1-4939-9794-7_17","article-title":"Use of liquid patient ascites fluids as a preclinical model for oncolytic virus activity","volume":"2058","author":"Scott","year":"2020","journal-title":"Methods Mol Biol"},{"key":"2025100308135275000_9.4.e001292.27","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.10.5538"},{"key":"2025100308135275000_9.4.e001292.28","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200316015"},{"key":"2025100308135275000_9.4.e001292.29","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2017.00961","article-title":"Functional expression of programmed death-ligand 1 (B7-H1) by immune cells and tumor cells","volume":"8","author":"Gibbons Johnson","year":"2017","journal-title":"Front Immunol"},{"key":"2025100308135275000_9.4.e001292.30","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3432"},{"key":"2025100308135275000_9.4.e001292.31","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1038\/mt.2014.22","article-title":"A phase 1 trial of oncolytic HSV-1, g207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses","volume":"22","author":"Markert","year":"2014","journal-title":"Mol Ther"},{"key":"2025100308135275000_9.4.e001292.32","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301205"},{"key":"2025100308135275000_9.4.e001292.33","unstructured":"HSV G207 in children with recurrent or refractory cerebellar brain tumors. Case Med Res 2019."},{"key":"2025100308135275000_9.4.e001292.34","doi-asserted-by":"publisher","DOI":"10.1111\/cas.13027"},{"key":"2025100308135275000_9.4.e001292.35","doi-asserted-by":"crossref","unstructured":"Kubota K , Moriyama M , Furukawa S , et al . CD163+CD204+ tumor-associated macrophages contribute to T cell regulation via interleukin-10 and PD-L1 production in oral squamous cell carcinoma. Sci Rep 2017;7.doi:10.1038\/s41598-017-01661-z","DOI":"10.1038\/s41598-017-01661-z"},{"key":"2025100308135275000_9.4.e001292.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-51149-1"},{"key":"2025100308135275000_9.4.e001292.37","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2019.1683347","article-title":"The M2 macrophage marker CD206: a novel prognostic indicator for acute myeloid leukemia","volume":"9","author":"Xu","year":"2020","journal-title":"Oncoimmunology"},{"key":"2025100308135275000_9.4.e001292.38","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20082173"},{"key":"2025100308135275000_9.4.e001292.39","doi-asserted-by":"publisher","DOI":"10.1038\/srep41926"},{"key":"2025100308135275000_9.4.e001292.40","doi-asserted-by":"crossref","first-page":"1700187","DOI":"10.1002\/mabi.201700187","article-title":"Solid tumor immunotherapy with T cell Engager-Armed oncolytic viruses","volume":"18","author":"Scott","year":"2018","journal-title":"Macromol Biosci"},{"key":"2025100308135275000_9.4.e001292.41","doi-asserted-by":"crossref","DOI":"10.1038\/srep36722","article-title":"B7-H1 antibodies lose antitumor activity due to activation of p38 MAPK that leads to apoptosis of tumor-reactive CD8+ T cells","volume":"6","author":"Liu","year":"2016","journal-title":"Sci Rep"},{"key":"2025100308135275000_9.4.e001292.42","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/s41590-020-0620-x","article-title":"Pd-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer","volume":"21","author":"Diskin","year":"2020","journal-title":"Nat Immunol"},{"key":"2025100308135275000_9.4.e001292.43","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.44.27802"},{"key":"2025100308135275000_9.4.e001292.44","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1080\/15384047.2018.1470722","article-title":"Animal models for studying tumor microenvironment (Tme) and resistance to lymphocytic infiltration","volume":"19","author":"Yamaguchi","year":"2018","journal-title":"Cancer Biol Ther"},{"key":"2025100308135275000_9.4.e001292.45","doi-asserted-by":"publisher","DOI":"10.1067\/msy.2001.114554"},{"key":"2025100308135275000_9.4.e001292.46","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2018.1535730","article-title":"Immune profiling and identification of prognostic immune-related risk factors in human ovarian cancer","volume":"8","author":"R\u00e5destad","year":"2019","journal-title":"Oncoimmunology"},{"key":"2025100308135275000_9.4.e001292.47","article-title":"Identification of thrombin-like activity in ovarian cancer associated ascites and modulation of multiple cytokine networks","volume":"106","author":"Naldini","year":"2011","journal-title":"Thromb Haemost"},{"key":"2025100308135275000_9.4.e001292.48","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00606"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2020-001292","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T15:14:01Z","timestamp":1759504441000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2020-001292"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3]]},"references-count":48,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4,5]]},"published-print":{"date-parts":[[2021,3]]}},"alternative-id":["10.1136\/jitc-2020-001292"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2020-001292","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3]]}}}