{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:39:31Z","timestamp":1790703571620,"version":"4.1.0"},"reference-count":32,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2020,2,7]],"date-time":"2020-02-07T00:00:00Z","timestamp":1581033600000},"content-version":"unspecified","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Malaghan Institute of Medical Research"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2020,1,21]]},"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Autologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r\/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r\/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r\/r B-NHL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>\n                      Eligible participants will be adults with r\/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2\u2009days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3\u2009dose escalation scheme is planned starting at 5\u00d710\n                      <jats:sup>4<\/jats:sup>\n                      \u2009CAR T-cells\/kg with a maximum dose of 1\u00d710\n                      <jats:sup>6<\/jats:sup>\n                      \u2009CAR T-cells\/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>Ethical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19\/STH\/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings.<\/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\" specific-use=\"clinicaltrial pre-results\" xlink:href=\"NCT04049513\">NCT04049513<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2019-034629","type":"journal-article","created":{"date-parts":[[2020,2,10]],"date-time":"2020-02-10T04:35:31Z","timestamp":1581309331000},"page":"e034629","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":52,"title":["Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE)"],"prefix":"10.1136","volume":"10","clinical-trial-number":[{"clinical-trial-number":"nct04049513","registry":"10.18810\/clinical-trials-gov","type":"preResults"},{"clinical-trial-number":"nct02822326","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04049513","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02822326","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02822326","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0184-2528","authenticated-orcid":false,"given":"Philip","family":"George","sequence":"first","affiliation":[{"name":"Cancer Immunotherapy Programme, Malaghan Institute of Medical Research, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel","family":"Dasyam","sequence":"additional","affiliation":[{"name":"Cancer Immunotherapy Programme, Malaghan 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