{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:43:08Z","timestamp":1792014188584,"version":"4.4.0"},"reference-count":46,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T00:00:00Z","timestamp":1656460800000},"content-version":"unspecified","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100031835","name":"Takara Bio Inc.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100031835","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["16im0110704s0104"],"award-info":[{"award-number":["16im0110704s0104"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Research and Development Programs Focused on Technology Transfer, Adaptable and Seamless Technology Transfer Program Through Target-driven"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,6,2]]},"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Because of the shortage of ideal cell surface antigens, the development of T-cell receptor (TCR)-engineered T cells (TCR-T) that target intracellular antigens such as NY-ESO-1 is a promising approach for treating patients with solid tumors. However, endogenous TCRs in vector-transduced T cells have been suggested to impair cell-surface expression of transduced TCR while generating mispaired TCRs that can become self-reactive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We conducted a first-in-human phase I clinical trial with the TCR-transduced T-cell product (TBI-1301) in patients with NY-ESO-1-expressing solid tumors. In manufacturing TCR-T cells, we used a novel affinity-enhanced NY-ESO-1-specific TCR that was transduced by a retroviral vector that enables siRNA (small interfering RNA)-mediated silencing of endogenous TCR. The patients were divided into two cohorts. Cohort 1 was given a dose of 5\u00d710\n                      <jats:sup>8<\/jats:sup>\n                      cells (whole cells including TCR-T cells) preconditioned with 1500 mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      cyclophosphamide. Cohort 2 was given 5\u00d7\u202f10\n                      <jats:sup>9<\/jats:sup>\n                      cells preconditioned with 1500 mg\/m\n                      <jats:sup>2<\/jats:sup>\n                      cyclophosphamide.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In vitro study showed that both the CD8\n                      <jats:sup>+<\/jats:sup>\n                      and CD4\n                      <jats:sup>+<\/jats:sup>\n                      T fractions of TCR-T cells exhibited cytotoxic effects against NY-ESO-1-expressing tumor cells. Three patients and six patients were allocated to cohort 1 and cohort 2, respectively. Three of the six patients who received 5\u00d710\n                      <jats:sup>9<\/jats:sup>\n                      cells showed tumor response, while three patients developed early-onset cytokine release syndrome (CRS). One of the patients developed a grade 3 lung injury associated with the infiltration of the TCR-T cells. No siRNA-related adverse events other than CRS were observed. Cytokines including interleukin 6 I and monocyte chemotactic protein-1\/chemokine (C-C motif) ligand (CCL2)\n                    <\/jats:p>\n                    <jats:p>increased in the sera of patients with CRS. In vitro analysis showed these cytokines were not secreted from the T cells infused. A significant fraction of the manufactured T cells in patients with CRS was found to express either CD244, CD39, or both at high levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The trial showed that endogenous TCR-silenced and affinity-enhanced NY-ESO-1 TCR-T cells were safely administered except for grade 3 lung injury. The TCR-T cell infusion exhibited significant tumor response and early-onset CRS in patients with tumors that express NY-ESO-1 at high levels. The differentiation properties of the manufactured T cells may be prognostic for TCR-T-related CRS.<\/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\" xlink:href=\"NCT02366546\">NCT02366546<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2021-003811","type":"journal-article","created":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T11:46:14Z","timestamp":1656503174000},"page":"e003811","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":67,"title":["NY-ESO-1-specific redirected T cells with endogenous TCR knockdown mediate tumor response and cytokine release syndrome"],"prefix":"10.1136","volume":"10","clinical-trial-number":[{"clinical-trial-number":"nct02366546","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02366546","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02366546","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7581-2615","authenticated-orcid":false,"given":"Mikiya","family":"Ishihara","sequence":"first","affiliation":[{"name":"Cancer Center, Mie University Hospital, Tsu, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4041-8298","authenticated-orcid":false,"given":"Shigehisa","family":"Kitano","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunotherapy Development, Advanced Medical Development Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan"},{"name":"Department of Experimental Therapeutics, National Cancer 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