{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T17:35:12Z","timestamp":1793036112508,"version":"4.5.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T00:00:00Z","timestamp":1731283200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T00:00:00Z","timestamp":1731283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Relapsed\/refractory peripheral T cell lymphomas (PTCLs) are aggressive tumors with a poor prognosis. Unlike B cell lymphomas, treatment of PTCL has not benefited from advances in immunotherapy. This is largely due to a lack of suitable target antigens that discriminate malignant from normal T cells, thus avoiding severe immunosuppression consequent to depletion of the entire T cell compartment. We recently described a targeting strategy based on the mutually exclusive expression of T cell antigen receptor beta-chain constant domain (TRBC) 1 and 2. Selective targeting of the T cell antigen receptor beta-chain expressed by the (clonal) malignancy spares normal T cells expressing the other chain. The LibraT1 study is an ongoing, multicenter, international, single-arm phase 1\/2 study of TRBC1-directed autologous chimeric antigen receptor (CAR) T cells (AUTO4) in relapsed\/refractory TRBC1-positive PTCL. Primary objectives were assessment of safety and tolerability of AUTO4 infusion. Key secondary endpoints included efficacy, CAR T cell expansion and persistence. Here we describe the findings from dose escalation in LibraT1 in the first ten patients, in a non-prespecified interim analysis. AUTO4 resulted in low frequency of severe immunotoxicity, with one of ten patients developing grade 3 cytokine release syndrome. Complete metabolic response was observed in four of ten evaluable patients, with remissions being durable beyond 1 year in two patients. While an absence of circulating CAR T cells was observed, CAR T cells were readily detected in lymph node biopsy samples from sites of original disease suggesting homing to tumor sites. These results support the continuing exploration of TRBC1 targeting in PTCL. ClinicalTrials.gov registration:\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT03590574\" ext-link-type=\"uri\">NCT03590574<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41591-024-03326-7","type":"journal-article","created":{"date-parts":[[2024,11,11]],"date-time":"2024-11-11T05:02:43Z","timestamp":1731301363000},"page":"137-143","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["TRBC1-CAR T cell therapy in peripheral T cell lymphoma: a phase 1\/2 trial"],"prefix":"10.1038","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9936-3431","authenticated-orcid":false,"given":"Kate","family":"Cwynarski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Iacoboni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Tholouli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Menne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Irvine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nivetha","family":"Balasubramaniam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh","family":"Wood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Basilico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarida","family":"Neves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meera","family":"Raymond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"El-Kholy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram","family":"Jha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather","family":"Dainton-Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rehan","family":"Hussain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Day","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8535-7348","authenticated-orcid":false,"given":"Mathieu","family":"Ferrari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koki","family":"Lilova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfram","family":"Brugger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Marafioti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Lao-Sirieix","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9757-8073","authenticated-orcid":false,"given":"Paul","family":"Maciocia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8347-9867","authenticated-orcid":false,"given":"Martin","family":"Pule","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,11]]},"reference":[{"key":"3326_CR1","doi-asserted-by":"publisher","first-page":"42","DOI":"10.5581\/1516-8484.20120013","volume":"34","author":"M Bellei","year":"2012","unstructured":"Bellei, M. et al. T-cell lymphomas in South America and Europe. Rev. Bras. Hematol. Hemoter. 34, 42\u201347 (2012).","journal-title":"Rev. Bras. Hematol. Hemoter."},{"key":"3326_CR2","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.3324\/haematol.2017.186577","volume":"103","author":"M Bellei","year":"2018","unstructured":"Bellei, M. et al. The outcome of peripheral T-cell lymphoma patients failing first-line therapy: a report from the prospective, International T-Cell Project. Haematologica 103, 1191\u20131197 (2018).","journal-title":"Haematologica"},{"key":"3326_CR3","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/S0140-6736(18)32984-2","volume":"393","author":"S Horwitz","year":"2019","unstructured":"Horwitz, S. et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet 393, 229\u2013240 (2019).","journal-title":"Lancet"},{"key":"3326_CR4","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1056\/NEJMoa2301665","volume":"389","author":"JR Westin","year":"2023","unstructured":"Westin, J. R. et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N. Engl. J. Med. 389, 148\u2013157 (2023).","journal-title":"N. Engl. J. Med."},{"key":"3326_CR5","doi-asserted-by":"publisher","first-page":"2472","DOI":"10.1200\/JCO.2005.03.6327","volume":"24","author":"P Went","year":"2006","unstructured":"Went, P. et al. Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J. Clin. Oncol. 24, 2472\u20132479 (2006).","journal-title":"J. Clin. Oncol."},{"key":"3326_CR6","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1038\/nm.4444","volume":"23","author":"PM Maciocia","year":"2017","unstructured":"Maciocia, P. M. et al. Targeting the T cell receptor \u03b2-chain constant region for immunotherapy of T cell malignancies. Nat. Med. 23, 1416\u20131423 (2017).","journal-title":"Nat. Med."},{"key":"3326_CR7","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1182\/blood-2014-01-545020","volume":"124","author":"B Philip","year":"2014","unstructured":"Philip, B. et al. A highly compact epitope-based marker\/suicide gene for easier and safer T-cell therapy. Blood 124, 1277\u20131287 (2014).","journal-title":"Blood"},{"key":"3326_CR8","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/sj.leu.2403302","volume":"18","author":"C Imai","year":"2004","unstructured":"Imai, C. et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676\u2013684 (2004).","journal-title":"Leukemia"},{"key":"3326_CR9","doi-asserted-by":"publisher","first-page":"3093","DOI":"10.1200\/JCO.2011.40.2719","volume":"30","author":"F d\u2019Amore","year":"2012","unstructured":"d\u2019Amore, F. et al. Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J. Clin. Oncol. 30, 3093\u20133099 (2012).","journal-title":"J. Clin. Oncol."},{"key":"3326_CR10","doi-asserted-by":"publisher","first-page":"100889","DOI":"10.1016\/j.blre.2021.100889","volume":"52","author":"A Mina","year":"2022","unstructured":"Mina, A. & Pro, B. T time: emerging and new therapies for peripheral T-cell lymphoma. Blood Rev. 52, 100889 (2022).","journal-title":"Blood Rev."},{"key":"3326_CR11","doi-asserted-by":"publisher","first-page":"1970","DOI":"10.1200\/JCO.2012.44.7524","volume":"31","author":"V Mak","year":"2013","unstructured":"Mak, V. et al. Survival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors. J. Clin. Oncol. 31, 1970\u20131976 (2013).","journal-title":"J. Clin. Oncol."},{"key":"3326_CR12","unstructured":"Patel, B. K., Basu, D., Kar, R. & Dubashi, B. Immunophenotyping of nodal peripheral T-cell lymphomas and its association with Epstein\u2013Barr virus. Iran. J. Blood Cancer 11, 101\u2013108 (2019)."},{"key":"3326_CR13","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1182\/blood-2019-129559","volume":"134","author":"LC Hill","year":"2019","unstructured":"Hill, L. C. et al. Safety and anti-tumor activity of CD5 CAR T-cells in patients with relapsed\/refractory T-cell malignancies. Blood 134, 199 (2019).","journal-title":"Blood"},{"key":"3326_CR14","unstructured":"Legend Biotech announces FDA clinical hold of its phase 1 clinical trial for LB1901. Business Wire https:\/\/www.businesswire.com\/news\/home\/20220215005555\/en (2022)."},{"key":"3326_CR15","doi-asserted-by":"publisher","unstructured":"Ong, S. Y. & Zain, J. M. Aggressive T-cell lymphomas: 2024: updates on diagnosis, risk stratification, and management. Am. J. Hematol. https:\/\/doi.org\/10.1002\/ajh.27165 (2024).","DOI":"10.1002\/ajh.27165"},{"key":"3326_CR16","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13045-023-01427-3","volume":"16","author":"Y Tan","year":"2023","unstructured":"Tan, Y. et al. Long-term follow-up of donor-derived CD7 CAR T-cell therapy in patients with T-cell acute lymphoblastic leukemia. J. Hematol. Oncol. 16, 34 (2023).","journal-title":"J. Hematol. Oncol."},{"key":"3326_CR17","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1158\/2159-8290.CD-15-0675","volume":"6","author":"A Trinquand","year":"2016","unstructured":"Trinquand, A. et al. Triggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemia. Cancer Discov. 6, 972\u2013985 (2016).","journal-title":"Cancer Discov."},{"key":"3326_CR18","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/s41375-021-01385-0","volume":"36","author":"PA Wawrzyniecka","year":"2022","unstructured":"Wawrzyniecka, P. A., Ibrahim, L., Gritti, G., Pule, M. A. & Maciocia, P. M. Chimeric antigen receptor T cells for gamma\u2013delta T cell malignancies. Leukemia 36, 577\u2013579 (2022).","journal-title":"Leukemia"},{"key":"3326_CR19","doi-asserted-by":"publisher","first-page":"2531","DOI":"10.1056\/NEJMoa1707447","volume":"377","author":"SS Neelapu","year":"2017","unstructured":"Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531\u20132544 (2017).","journal-title":"N. Engl. J. Med."},{"key":"3326_CR20","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.ymthe.2022.09.003","volume":"31","author":"N Watanabe","year":"2023","unstructured":"Watanabe, N. et al. Feasibility and preclinical efficacy of CD7-unedited CD7 CAR T cells for T cell malignancies. Mol. Ther. 31, 24\u201334 (2023).","journal-title":"Mol. Ther."},{"key":"3326_CR21","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.omtm.2022.12.006","volume":"28","author":"L Mekkaoui","year":"2023","unstructured":"Mekkaoui, L. et al. Efficient clinical-grade \u03b3-retroviral vector purification by high-speed centrifugation for CAR T cell manufacturing. Mol. Ther. Methods Clin. Dev. 28, 116\u2013128 (2023).","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"3326_CR22","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1016\/j.bbmt.2018.12.758","volume":"25","author":"DW Lee","year":"2019","unstructured":"Lee, D. W. et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transplant. 25, 625\u2013638 (2019).","journal-title":"Biol. Blood Marrow Transplant."},{"key":"3326_CR23","first-page":"47\u201362","volume":"15","author":"SS Neelapu","year":"2018","unstructured":"Neelapu, S. S. et al. Chimeric antigen receptor T-cell therapy\u2014assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47\u201362 (2018).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"3326_CR24","doi-asserted-by":"publisher","first-page":"3059","DOI":"10.1200\/JCO.2013.54.8800","volume":"32","author":"BD Cheson","year":"2014","unstructured":"Cheson, B. D. et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J. Clin. Oncol. 32, 3059\u20133068 (2014).","journal-title":"J. Clin. Oncol."}],"container-title":["Nature Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03326-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03326-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03326-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T18:03:48Z","timestamp":1737482628000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41591-024-03326-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,11]]},"references-count":24,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1]]}},"alternative-id":["3326"],"URL":"https:\/\/doi.org\/10.1038\/s41591-024-03326-7","relation":{},"ISSN":["1078-8956","1546-170X"],"issn-type":[{"value":"1078-8956","type":"print"},{"value":"1546-170X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,11]]},"assertion":[{"value":"18 January 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 September 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 November 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"K.C.: consulting\/advisory role: Roche, Takeda, Celgene, Atara, Gilead, KITE, Janssen, Incyte and AbbVie; speakers\u2019 bureau: Roche, Takeda, KITE, Gilead and Incyte; conferences\/travel support: Roche, Takeda, KITE, Janssen and BMS. G.I.: honoraria and travel support: Novartis, Kite\/Gilead, Bristol Myers Squibb, AbbVie, Autolus, Sandoz, Miltenyi and AstraZeneca. E.T.: speaker fees: Astellas, Jazz, Kite\/Gilead, Pfizer and Vertex; ad boards: Autolus, BMS\/Celgene, Jazz, Janssen and Vertex. M.P.: owns stock in and has research funding and salary contribution from Autolus. D.I.: travel grants and honoraria: Kite\/Gilead and Janssen. T.M.: travel grants: Amgen, Jazz, Pfizer, Bayer, Kyowa Kirin, Celgene\/BMS, Kite\/Gilead, Janssen and Takeda; honoraria for advisory board meetings: Kite\/Gilead, Amgen, Novartis, Pfizer, Celgene\/BMS, Daiichi Sankyo, Atara, Roche and Janssen; honoraria for lectures: Kite\/Gilead, Takeda, Janssen, Roche, Servier, Novartis, Celgene\/BMS, Pfizer and Incyte; research funding: Janssen, AstraZeneca and Novartis. T.M.: consulting\/advisory role: Roche\/Ventana, Haematogenix and Autolus. P.M.: Autolus: stock holder and research funding. UCL business: patent royalties. All employees of Autolus have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}