{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:59:45Z","timestamp":1790996385355,"version":"4.1.0"},"reference-count":38,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2023,11,10]],"date-time":"2023-11-10T00:00:00Z","timestamp":1699574400000},"content-version":"unspecified","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["2021-13673"],"award-info":[{"award-number":["2021-13673"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017646","name":"Ovacure Foundation","doi-asserted-by":"publisher","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/100017646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,10,17]]},"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The presence of T cells and suppressive myeloid cells in epithelial ovarian cancer (EOC) correlate with good and bad clinical outcome, respectively. This suggests that EOC may be sensitive to adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL), provided that immunosuppression by myeloid-derived suppressor cells and M2 macrophages is reduced. Platinum-based chemotherapy can alleviate such immunosuppression, potentially creating a window of opportunity for T cell-based immunotherapy.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We initiated a phase I\/II trial (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04072263\">NCT04072263<\/jats:ext-link>) in patients with recurrent platinum-sensitive EOC receiving TIL during platinum-based chemotherapy. TILs were administered 2\u2009weeks after the second, third and fourth chemotherapy course. Patients were treated in two cohorts with or without interferon-\u03b1 (IFNa), as conditioning and TIL support regimen. The primary endpoint was to evaluate the feasibility and safety according to CTCAE V.4.03 criteria and the clinical response and immune modulatory effects of this treatment were evaluated as secondary endpoints.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Sixteen patients were enrolled. TIL could be successfully expanded for all patients. TIL treatment during chemotherapy without IFNa (n=13) was safe but the combination with IFNa added to the chemotherapy-induced toxicity with 2 out of 3 patients developing thrombocytopenia as dose-limiting toxicity. Fourteen patients completed treatment with a full TIL cycle and were further evaluated for clinical and immunological response. Platinum-based chemotherapy resulted in reduction of circulating myeloid cell numbers and IL-6 plasma levels, confirming its immunosuppression-alleviating effect. Three complete (CR), nine partial responses and two stable diseases were recorded, resulting in an objective response rate of 86% (Response Evaluation Criteria In Solid Tumors V.1.1). Interestingly, progression free survival that exceeded the previous platinum-free interval was detected in two patients, including an exceptionally long and ongoing CR in one patient that coincided with sustained alleviation of immune suppression.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>TIL therapy can be safely combined with platinum-based chemotherapy but not in combination with IFNa. The chemotherapy-mediated reduction in immunosuppression and the increase in platinum-free interval for two patients warrants further exploration of properly-timed TIL infusions during platinum-based chemotherapy, possibly further benefiting from IL-2 support, as a novel treatment option for EOC patients.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2023-007697","type":"journal-article","created":{"date-parts":[[2023,11,10]],"date-time":"2023-11-10T12:10:47Z","timestamp":1699618247000},"page":"e007697","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":27,"title":["Timed adoptive T cell transfer during chemotherapy in patients with recurrent platinum-sensitive epithelial ovarian cancer"],"prefix":"10.1136","volume":"11","clinical-trial-number":[{"clinical-trial-number":"nct04072263","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04072263","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04072263","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4449-8707","authenticated-orcid":false,"given":"Els M E","family":"Verdegaal","sequence":"first","affiliation":[{"name":"Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2874-4402","authenticated-orcid":false,"given":"Saskia J","family":"Santegoets","sequence":"additional","affiliation":[{"name":"Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marij J P","family":"Welters","sequence":"additional","affiliation":[{"name":"Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"de Bruin","sequence":"additional","affiliation":[{"name":"Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marten","family":"Visser","sequence":"additional","affiliation":[{"name":"Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline E","family":"van der Minne","sequence":"additional","affiliation":[{"name":"Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pita M","family":"de Kok","sequence":"additional","affiliation":[{"name":"Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikki M","family":"Loof","sequence":"additional","affiliation":[{"name":"Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanne","family":"Boekestijn","sequence":"additional","affiliation":[{"name":"Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge","family":"Roozen","sequence":"additional","affiliation":[{"name":"Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge M","family":"Westra","sequence":"additional","affiliation":[{"name":"Center for Cell and Gene Therapy, Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Meij","sequence":"additional","affiliation":[{"name":"Center for Cell and Gene Therapy, Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6556-0354","authenticated-orcid":false,"given":"Sjoerd H","family":"Van der Burg","sequence":"additional","affiliation":[{"name":"Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2671-1903","authenticated-orcid":false,"given":"Judith R","family":"Kroep","sequence":"additional","affiliation":[{"name":"Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,11,10]]},"reference":[{"key":"2025100300491621000_11.11.e007697.1","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1200\/JCO.22.01549","article-title":"Overall survival with maintenance Olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the Solo1\/GOG 3004 trial","volume":"41","author":"DiSilvestro","year":"2023","journal-title":"J Clin Oncol"},{"key":"2025100300491621000_11.11.e007697.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020177"},{"key":"2025100300491621000_11.11.e007697.3","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1097\/CJI.0b013e31821e012f","article-title":"Tumor-infiltrating cytotoxic T lymphocytes as independent prognostic factor in epithelial ovarian cancer with Wilms tumor protein 1 overexpression","volume":"34","author":"Vermeij","year":"2011","journal-title":"J Immunother"},{"key":"2025100300491621000_11.11.e007697.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2011.09.039"},{"key":"2025100300491621000_11.11.e007697.5","doi-asserted-by":"publisher","DOI":"10.1038\/nm1093"},{"key":"2025100300491621000_11.11.e007697.6","doi-asserted-by":"crossref","DOI":"10.4161\/21624011.2014.962397","article-title":"Interleukin-6 receptor and its ligand Interleukin-6 are opposite markers for survival and infiltration with mature myeloid cells in ovarian cancer","volume":"3","author":"Wouters","year":"2014","journal-title":"Oncoimmunology"},{"key":"2025100300491621000_11.11.e007697.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.08.025"},{"key":"2025100300491621000_11.11.e007697.8","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.20164"},{"key":"2025100300491621000_11.11.e007697.9","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-2449"},{"key":"2025100300491621000_11.11.e007697.10","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2018.1465166","article-title":"The blood mMDSC to DC ratio is a sensitive and easy to assess independent predictive factor for epithelial ovarian cancer survival","volume":"7","author":"Santegoets","year":"2018","journal-title":"Oncoimmunology"},{"key":"2025100300491621000_11.11.e007697.11","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ejogrb.2007.05.012","article-title":"Pre-treatment white blood cell subtypes as prognostic indicators in ovarian cancer","volume":"138","author":"Bishara","year":"2008","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"2025100300491621000_11.11.e007697.12","doi-asserted-by":"crossref","first-page":"538","DOI":"10.7150\/jca.14206","article-title":"The lymphocyte-monocyte ratio predicts patient survival and aggressiveness of ovarian cancer","volume":"7","author":"Eo","year":"2016","journal-title":"J Cancer"},{"key":"2025100300491621000_11.11.e007697.13","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.tranon.2016.10.006","article-title":"Preoperative monocyte-to-lymphocyte ratio in peripheral blood predicts stages, metastasis, and histological grades in patients with ovarian cancer","volume":"10","author":"Xiang","year":"2017","journal-title":"Transl Oncol"},{"key":"2025100300491621000_11.11.e007697.14","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-009-0749-9"},{"key":"2025100300491621000_11.11.e007697.15","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aad8307","article-title":"Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses","volume":"8","author":"Welters","year":"2016","journal-title":"Sci Transl Med"},{"key":"2025100300491621000_11.11.e007697.16","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1126\/scitranslmed.aaz8235","article-title":"Strong vaccine responses during chemotherapy are associated with prolonged cancer survival","volume":"12","author":"Melief","year":"2020","journal-title":"Sci Transl Med"},{"key":"2025100300491621000_11.11.e007697.17","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-0116"},{"key":"2025100300491621000_11.11.e007697.18","doi-asserted-by":"crossref","DOI":"10.1186\/1479-5876-10-169","article-title":"Adoptive cell therapy with Autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients","volume":"10","author":"Ellebaek","year":"2012","journal-title":"J Transl Med"},{"key":"2025100300491621000_11.11.e007697.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01462-y"},{"key":"2025100300491621000_11.11.e007697.20","doi-asserted-by":"crossref","DOI":"10.1080\/2162402X.2018.1502905","article-title":"Adoptive cell therapy with tumor-infiltrating lymphocytes in patients with metastatic ovarian cancer: a pilot study","volume":"7","author":"Pedersen","year":"2018","journal-title":"Oncoimmunology"},{"key":"2025100300491621000_11.11.e007697.21","first-page":"501","article-title":"Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes","volume":"1","author":"Fujita","year":"1995","journal-title":"Clin Cancer Res"},{"key":"2025100300491621000_11.11.e007697.22","first-page":"1934","article-title":"Use of adoptive transfer of tumor-infiltrating lymphocytes alone or in combination with cisplatin-containing chemotherapy in patients with epithelial ovarian cancer","volume":"51","author":"Aoki","year":"1991","journal-title":"Cancer Res"},{"key":"2025100300491621000_11.11.e007697.23","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.00.240"},{"key":"2025100300491621000_11.11.e007697.24","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.16.5449"},{"key":"2025100300491621000_11.11.e007697.25","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2019-000166","article-title":"Low-dose interferon-alpha preconditioning and adoptive cell therapy in patients with metastatic melanoma refractory to standard (immune) therapies: a phase I\/II study","volume":"8","author":"Verdegaal","year":"2020","journal-title":"J Immunother Cancer"},{"key":"2025100300491621000_11.11.e007697.26","doi-asserted-by":"publisher","DOI":"10.1126\/science.1076514"},{"key":"2025100300491621000_11.11.e007697.27","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/s41588-023-01320-2","article-title":"Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer","volume":"55","author":"Burdett","year":"2023","journal-title":"Nat Genet"},{"key":"2025100300491621000_11.11.e007697.28","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-015-1729-x"},{"key":"2025100300491621000_11.11.e007697.29","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.25.7519"},{"key":"2025100300491621000_11.11.e007697.30","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)13718-X"},{"key":"2025100300491621000_11.11.e007697.31","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2004.05.195"},{"key":"2025100300491621000_11.11.e007697.32","doi-asserted-by":"crossref","unstructured":"Milne K , Alexander C , Webb JR , et al . Absolute lymphocyte count is associated with survival in ovarian cancer independent of tumor-infiltrating lymphocytes. J Transl Med 2012;10. doi:10.1186\/1479-5876-10-33","DOI":"10.1186\/1479-5876-10-33"},{"key":"2025100300491621000_11.11.e007697.33","doi-asserted-by":"crossref","DOI":"10.3390\/diagnostics11071298","article-title":"Decrease in neutrophil-to-lymphocyte ratio during neoadjuvant chemotherapy as a predictive and prognostic marker in advanced ovarian cancer","volume":"11","author":"Sanna","year":"2021","journal-title":"Diagnostics (Basel)"},{"key":"2025100300491621000_11.11.e007697.34","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2017.01840","article-title":"Interleukin-6 Trans-signaling pathway promotes immunosuppressive myeloid-derived suppressor cells via suppression of suppressor of cytokine signaling 3 in breast cancer","volume":"8","author":"Jiang","year":"2017","journal-title":"Front Immunol"},{"key":"2025100300491621000_11.11.e007697.35","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-3542"},{"key":"2025100300491621000_11.11.e007697.36","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdv309"},{"key":"2025100300491621000_11.11.e007697.37","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.adg3736","article-title":"Monocytic Mdscs exhibit superior immune suppression via adenosine and depletion of adenosine improves efficacy of immunotherapy","volume":"9","author":"Sarkar","year":"2023","journal-title":"Sci Adv"},{"key":"2025100300491621000_11.11.e007697.38","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0193829","article-title":"Expression of PD-1 and Tim-3 markers of T-cell exhaustion is associated with Cd4 Dynamics during the course of untreated and treated HIV infection","volume":"13","author":"Rall\u00f3n","year":"2018","journal-title":"PLoS One"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2023-007697","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T07:49:26Z","timestamp":1759477766000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2023-007697"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11]]},"references-count":38,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11,10]]},"published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.1136\/jitc-2023-007697"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2023-007697","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11]]}}}