{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:00:33Z","timestamp":1791896433663,"version":"4.3.4"},"reference-count":19,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T00:00:00Z","timestamp":1622592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T00:00:00Z","timestamp":1622592000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>HBV\u2010specific T\u2010cell receptor (HBV\u2010TCR) engineered T cells have the potential for treating HCC relapses after liver transplantation, but their efficacy can be hampered by the concomitant immunosuppressive treatment required to prevent graft rejection. Our aim is to molecularly engineer TCR\u2010T cells that could retain their polyfunctionality in such patients while minimizing the associated risk of organ rejection.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>We first analyzed how immunosuppressive drugs can interfere with the <jats:italic toggle=\"yes\">in vivo<\/jats:italic> function of TCR\u2010T cells in liver transplanted patients with HBV\u2010HCC recurrence receiving HBV\u2010TCR T cells and <jats:italic toggle=\"yes\">in vitro<\/jats:italic> in the presence of clinically relevant concentrations of immunosuppressive tacrolimus (TAC) and mycophenolate mofetil (MMF). Immunosuppressive Drug Resistant Armored TCR\u2010T cells of desired specificity (HBV or Epstein\u2010Barr virus) were then engineered by concomitantly electroporating mRNA encoding specific TCRs and mutated variants of calcineurin B (CnB) and inosine\u20105\u2032\u2010monophosphate dehydrogenase (IMPDH), and their function was assessed through intracellular cytokine staining and cytotoxicity assays in the presence of TAC and MMF. Liver transplanted HBV\u2010HCC patients receiving different immunosuppressant drugs exhibited varying levels of activated (CD39<jats:sup>+<\/jats:sup> Ki67<jats:sup>+<\/jats:sup>) peripheral blood mononuclear cells after HBV\u2010TCR T\u2010cell infusions that positively correlate with clinical efficacy. <jats:italic toggle=\"yes\">In vitro<\/jats:italic> experiments with TAC and MMF showed a potent inhibition of TCR\u2010T cell polyfunctionality. This inhibition can be effectively negated by the transient overexpression of mutated variants of CnB and IMPDH. Importantly, the resistance only lasted for 3\u20105\u00a0days, after which sensitivity was restored.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>We engineered TCR\u2010T cells of desired specificities that transiently escape the immunosuppressive effects of TAC and MMF. This finding has important clinical applications for the treatment of HBV\u2010HCC relapses and other pathologies occurring in organ transplanted patients.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31662","type":"journal-article","created":{"date-parts":[[2020,11,29]],"date-time":"2020-11-29T03:21:05Z","timestamp":1606620065000},"page":"200-213","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":56,"title":["Immunosuppressive Drug\u2010Resistant Armored T\u2010Cell Receptor T Cells for Immune Therapy of HCC in Liver Transplant Patients"],"prefix":"10.1097","volume":"74","author":[{"given":"Morteza","family":"Hafezi","sequence":"first","affiliation":[{"name":"Emerging Infectious Diseases Program,Duke\u2010NUS Medical School,Singapore,Singapore"},{"name":"Department of Paediatrics,Yong Loo Lin School of Medicine,National University of Singapore,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiyin","family":"Lin","sequence":"additional","affiliation":[{"name":"Emerging Infectious Diseases Program,Duke\u2010NUS Medical School,Singapore,Singapore"},{"name":"Institute of Molecular and Cell Biology,Agency for Science and Technology,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeline","family":"Chia","sequence":"additional","affiliation":[{"name":"Emerging Infectious Diseases Program,Duke\u2010NUS Medical School,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alicia","family":"Chua","sequence":"additional","affiliation":[{"name":"Lion TCR Pte Ltd,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi Zong","family":"Ho","sequence":"additional","affiliation":[{"name":"Lion TCR Pte Ltd,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Royce","family":"Fam","sequence":"additional","affiliation":[{"name":"Lion TCR Pte Ltd,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Tan","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology,Agency for Science and Technology,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joey","family":"Aw","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology,Agency for Science and Technology,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Pavesi","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Cell Biology,Agency for Science and Technology,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thinesh Lee","family":"Krishnamoorthy","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology & Hepatology,Singapore General Hospital,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan Cheng","family":"Chow","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology & Hepatology,Singapore General Hospital,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biotherapy,The Third Affiliated Hospital of Sun Yat\u2010Sen University,Guandong,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biotherapy,The Third Affiliated Hospital of Sun Yat\u2010Sen University,Guandong,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu\u2010En","family":"Wai","sequence":"additional","affiliation":[{"name":"Lion TCR Pte Ltd,Singapore,Singapore"},{"name":"Singapore Immunology Network,Agency for Science and Technology,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarene","family":"Koh","sequence":"additional","affiliation":[{"name":"Lion TCR Pte Ltd,Singapore,Singapore"},{"name":"Singapore Immunology Network,Agency for Science and Technology,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony T.","family":"Tan","sequence":"additional","affiliation":[{"name":"Emerging Infectious Diseases Program,Duke\u2010NUS Medical School,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2942-0485","authenticated-orcid":false,"given":"Antonio","family":"Bertoletti","sequence":"additional","affiliation":[{"name":"Emerging Infectious Diseases Program,Duke\u2010NUS Medical School,Singapore,Singapore"},{"name":"Singapore Immunology Network,Agency for Science and Technology,Singapore,Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,6,2]]},"reference":[{"key":"hep31662-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1053\/j.gastro.2011.12.061","article-title":"Epidemiology of viral hepatitis and hepatocellular carcinoma","volume":"142","year":"2012","journal-title":"Gastroenterology"},{"key":"hep31662-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1056\/NEJM199603143341104","article-title":"Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis","volume":"334","year":"1996","journal-title":"N Engl J Med"},{"key":"hep31662-bib-0003-20250824","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1016\/j.jhep.2012.06.033","article-title":"Recurrence of hepatocellular cancer after liver transplantation: the role of primary resection and salvage transplantation in East and West","volume":"57","year":"2012","journal-title":"J Hepatol"},{"key":"hep31662-bib-0004-20250824","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.jamcollsurg.2014.12.025","article-title":"A novel prognostic nomogram accurately predicts hepatocellular carcinoma recurrence after liver transplantation: analysis of 865 consecutive liver transplant recipients","volume":"220","year":"2015","journal-title":"J Am Coll Surg"},{"key":"hep31662-bib-0005-20250824","doi-asserted-by":"crossref","first-page":"261","DOI":"10.4254\/wjh.v11.i3.261","article-title":"Hepatocellular carcinoma recurrence after liver transplantation: risk factors, screening and clinical presentation","volume":"11","year":"2019","journal-title":"World J Hep"},{"key":"hep31662-bib-0006-20250824","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.jhep.2005.07.019","article-title":"How should patients with hepatocellular carcinoma recurrence after liver transplantation be treated?","volume":"43","year":"2005","journal-title":"J Hepatol"},{"key":"hep31662-bib-0007-20250824","article-title":"Salvage liver transplantation is a reasonable option for selected patients who have recurrent hepatocellular carcinoma after liver resection","volume":"7","year":"2012","journal-title":"PLoS One"},{"key":"hep31662-bib-0008-20250824","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1056\/NEJMoa1915745","article-title":"Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma","volume":"382","year":"2020","journal-title":"N Engl J Med"},{"key":"hep31662-bib-0009-20250824","article-title":"Liver graft rejection following immune checkpoint inhibitors treatment: a review","volume":"36","year":"2019","journal-title":"Med Oncol"},{"key":"hep31662-bib-0010-20250824","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1053\/j.gastro.2019.01.251","article-title":"Use of expression profiles of HBV\u2010DNA integrated into genomes of hepatocellular carcinoma cells to select T cells for immunotherapy","volume":"156","year":"2019","journal-title":"Gastroenterology"},{"key":"hep31662-bib-0011-20250824","article-title":"Personalized T\u2010cell therapy in liver transplanted patients with hepatitis B virus related hepatocellular carcinoma","volume":"2020","year":"2020","journal-title":"Hepatoma Res"},{"key":"hep31662-bib-0012-20250824","first-page":"S1","article-title":"Present state of immunosuppressive therapy in liver transplant recipients","volume":"17(Suppl. 3)","year":"2011","journal-title":"Liver Transpl"},{"key":"hep31662-bib-0013-20250824","article-title":"A 3D microfluidic model for preclinical evaluation of TCR\u2010engineered T cells against solid tumors","volume":"2","year":"2017","journal-title":"JCI Insight"},{"key":"hep31662-bib-0014-20250824","first-page":"1103","article-title":"Engineering virus\u2010specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines","volume":"55","year":"2011","journal-title":"J Hepatol"},{"key":"hep31662-bib-0015-20250824","doi-asserted-by":"crossref","first-page":"4792","DOI":"10.1182\/blood-2009-07-228387","article-title":"Generation of EBV\u2010specific cytotoxic T cells that are resistant to calcineurin inhibitors for the treatment of posttransplantation lymphoproliferative disease","volume":"114","year":"2009","journal-title":"Blood"},{"key":"hep31662-bib-0016-20250824","doi-asserted-by":"crossref","first-page":"3244","DOI":"10.1111\/ajt.12475","article-title":"Rapid generation of EBV\u2010specific cytotoxic T lymphocytes resistant to calcineurin inhibitors for adoptive immunotherapy","volume":"13","year":"2013","journal-title":"Am J Transplant"},{"key":"hep31662-bib-0017-20250824","article-title":"Engineering human T cells for resistance to methotrexate and mycophenolate mofetil as an in vivo cell selection strategy","volume":"8","year":"2013","journal-title":"PLoS One"},{"key":"hep31662-bib-0018-20250824","article-title":"Building and optimizing a virus\u2010specific T cell receptor library for targeted immunotherapy in viral infections","volume":"4","year":"2014","journal-title":"Sci Rep"},{"key":"hep31662-bib-0019-20250824","doi-asserted-by":"crossref","first-page":"2513","DOI":"10.1172\/JCI90599","article-title":"Immunotherapy for transplantation\u2010associated viral infections","volume":"127","year":"2017","journal-title":"J Clin Invest"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.31662","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.31662","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31662","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T23:06:48Z","timestamp":1756076808000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31662"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,2]]},"references-count":19,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.31662","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,2]]},"assertion":[{"value":"2020-09-23","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-11-16","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}