{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T04:59:57Z","timestamp":1789275597076,"version":"build-2803163510"},"reference-count":43,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T00:00:00Z","timestamp":1688083200000},"content-version":"unspecified","delay-in-days":29,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Autolus Therapeutics","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/S001883\/1"],"award-info":[{"award-number":["MR\/S001883\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,5,26]]},"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>We used a proliferating ligand (APRIL) to construct a ligand-based third generation chimeric antigen receptor (CAR) able to target two myeloma antigens, B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The APRIL CAR was evaluated in a Phase 1 clinical trial (\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT03287804\">NCT03287804<\/jats:ext-link>\n                      , AUTO2) in patients with relapsed, refractory multiple myeloma. Eleven patients received 13 doses, the first 15\u00d710\n                      <jats:sup>6<\/jats:sup>\n                      CARs, and subsequent patients received 75,225,600 and 900\u00d710\n                      <jats:sup>6<\/jats:sup>\n                      CARs in a 3+3 escalation design.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The APRIL CAR was well tolerated. Five (45.5%) patients developed Grade 1 cytokine release syndrome and there was no neurotoxicity. However, responses were only observed in 45.5% patients (1\u00d7very good partial response, 3\u00d7partial response, 1\u00d7minimal response). Exploring the mechanistic basis for poor responses, we then compared the APRIL CAR to two other BCMA CARs in a series of in vitro assays, observing reduced interleukin-2 secretion and lack of sustained tumor control by APRIL CAR regardless of transduction method or co-stimulatory domain. There was also impaired interferon signaling of APRIL CAR and no evidence of autoactivation. Thus focusing on APRIL itself, we confirmed similar affinity to BCMA and protein stability in comparison to BCMA CAR binders but reduced binding by cell-expressed APRIL to soluble BCMA and reduced avidity to tumor cells. This indicated either suboptimal folding or stability of membrane-bound APRIL attenuating CAR activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The APRIL CAR was well tolerated, but the clinical responses observed in AUTO2 were disappointing. Subsequently, when comparing the APRIL CAR to other BCMA CARs, we observed in vitro functional deficiencies due to reduced target binding by cell-expressed ligand.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2023-006699","type":"journal-article","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T14:40:30Z","timestamp":1688136030000},"page":"e006699","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["Limited efficacy of APRIL CAR in patients with multiple myeloma indicate challenges in the use of natural ligands for CAR T-cell therapy"],"prefix":"10.1136","volume":"11","clinical-trial-number":[{"clinical-trial-number":"nct03287804","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03287804","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6092-8949","authenticated-orcid":false,"given":"Lydia","family":"Lee","sequence":"first","affiliation":[{"name":"Research Department of Haematology, UCL Cancer Institute, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen Chean","family":"Lim","sequence":"additional","affiliation":[{"name":"Autolus Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Galas-Filipowicz","sequence":"additional","affiliation":[{"name":"Research Department of Haematology, UCL Cancer Institute, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kent","family":"Fung","sequence":"additional","affiliation":[{"name":"Research Department of Haematology, UCL Cancer Institute, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Taylor","sequence":"additional","affiliation":[{"name":"Autolus Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Pathology, UCL Cancer Institute, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zulaikha","family":"Akbar","sequence":"additional","affiliation":[{"name":"Autolus Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Alvarez Mediavilla","sequence":"additional","affiliation":[{"name":"Research Department of Haematology, UCL Cancer Institute, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrycja","family":"Wawrzyniecka","sequence":"additional","affiliation":[{"name":"Lumicks, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debarati","family":"Shome","sequence":"additional","affiliation":[{"name":"Lumicks, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7471-7715","authenticated-orcid":false,"given":"Rogier M","family":"Reijmers","sequence":"additional","affiliation":[{"name":"Lumicks, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trillian","family":"Gregg","sequence":"additional","affiliation":[{"name":"Lumicks, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leigh","family":"Wood","sequence":"additional","affiliation":[{"name":"Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Day","sequence":"additional","affiliation":[{"name":"Autolus Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Cerec","sequence":"additional","affiliation":[{"name":"Autolus Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Autolus Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Thomas","sequence":"additional","affiliation":[{"name":"Autolus Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaun","family":"Cordoba","sequence":"additional","affiliation":[{"name":"Autolus Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimobi","family":"Onuoha","sequence":"additional","affiliation":[{"name":"Autolus Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nushmia","family":"Khokhar","sequence":"additional","affiliation":[{"name":"Autolus Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Peddareddigari","sequence":"additional","affiliation":[{"name":"Autolus Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Al-Hajj","sequence":"additional","affiliation":[{"name":"Autolus Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Cavet","sequence":"additional","affiliation":[{"name":"The Christie NHS Foundation Trust, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Zweegman","sequence":"additional","affiliation":[{"name":"Vrije Univ Amsterdam, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Rodriguez-Justo","sequence":"additional","affiliation":[{"name":"Department of Pathology, UCL Cancer Institute, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwee","family":"Yong","sequence":"additional","affiliation":[{"name":"Research Department of Haematology, UCL Cancer Institute, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Pule","sequence":"additional","affiliation":[{"name":"Research Department of Haematology, UCL Cancer Institute, London, UK"},{"name":"Autolus Ltd, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh","family":"Popat","sequence":"additional","affiliation":[{"name":"Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2023,6,30]]},"reference":[{"key":"2025100309313490000_11.6.e006699.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709866"},{"key":"2025100309313490000_11.6.e006699.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707447"},{"key":"2025100309313490000_11.6.e006699.3","doi-asserted-by":"crossref","DOI":"10.1016\/j.blre.2022.100929","article-title":"Current state and next-generation CAR-T cells in multiple myeloma","volume":"54","author":"Manier","year":"2022","journal-title":"Blood Rev"},{"key":"2025100309313490000_11.6.e006699.4","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14145"},{"key":"2025100309313490000_11.6.e006699.5","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-05-781351"},{"key":"2025100309313490000_11.6.e006699.6","doi-asserted-by":"crossref","DOI":"10.1182\/blood-2019-126218","article-title":"Cd19-loss with preservation of other B cell lineage features in patients with large B cell lymphoma who Relapsed post-Axi-Cel","volume":"134","author":"Neelapu","year":"2019","journal-title":"Blood"},{"key":"2025100309313490000_11.6.e006699.7","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4441"},{"key":"2025100309313490000_11.6.e006699.8","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-04-711903"},{"key":"2025100309313490000_11.6.e006699.9","doi-asserted-by":"publisher","DOI":"10.1172\/JCI126397"},{"key":"2025100309313490000_11.6.e006699.10","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-021-21177-5","article-title":"Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma","volume":"12","author":"Samur","year":"2021","journal-title":"Nat Commun"},{"key":"2025100309313490000_11.6.e006699.11","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-05-552729"},{"key":"2025100309313490000_11.6.e006699.12","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-82-5-1027"},{"key":"2025100309313490000_11.6.e006699.13","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/S0140-6736(21)00933-8","article-title":"Ciltacabtagene Autoleucel, a B-cell maturation antigen-directed Chimeric antigen receptor T-cell therapy in patients with Relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1B\/2 open-label study","volume":"398","author":"Berdeja","year":"2021","journal-title":"Lancet"},{"key":"2025100309313490000_11.6.e006699.14","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2024850"},{"key":"2025100309313490000_11.6.e006699.15","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-2422"},{"key":"2025100309313490000_11.6.e006699.16","doi-asserted-by":"crossref","DOI":"10.1182\/blood.V126.23.3094.3094","article-title":"A novel and highly potent CAR T cell drug product for treatment of BCMA-expressing hematological Malignances","volume":"126","author":"Chekmasova","year":"2015","journal-title":"Blood"},{"key":"2025100309313490000_11.6.e006699.17","unstructured":"Morgan R , Friedman K . Bcma Chimeric antigen receptors. Wo2016094304A2. 2016. Available: https:\/\/patents.google.com\/patent\/WO2016094304A2\/en?oq=WO+2016%2f094304+A2+"},{"key":"2025100309313490000_11.6.e006699.18","unstructured":"Fan X , Zhuang Q , Wang P , et al . Chimeric antigen receptors targeting Bcma and methods of use thereof. Wo2018028647A1. 2018. Available: https:\/\/patents.google.com\/patent\/WO2018028647A1\/en?oq=WO2018028647A1"},{"key":"2025100309313490000_11.6.e006699.19","unstructured":"Ubani EZ . Bcma-targeted car-t cell therapy of multiple myeloma. 2021. Available: https:\/\/patents.google.com\/patent\/US20210128618A1\/en?oq=US20210128618A1"},{"key":"2025100309313490000_11.6.e006699.20","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2710"},{"key":"2025100309313490000_11.6.e006699.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2006.04.006"},{"key":"2025100309313490000_11.6.e006699.22","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000703"},{"key":"2025100309313490000_11.6.e006699.23","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-19-1109"},{"key":"2025100309313490000_11.6.e006699.24","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.00842"},{"key":"2025100309313490000_11.6.e006699.25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1819745116"},{"key":"2025100309313490000_11.6.e006699.26","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2018.77.8084"},{"key":"2025100309313490000_11.6.e006699.27","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1817226"},{"key":"2025100309313490000_11.6.e006699.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcyt.2014.12.002"},{"key":"2025100309313490000_11.6.e006699.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0010-1"},{"key":"2025100309313490000_11.6.e006699.30","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1182\/blood-2020-140410","article-title":"Updated results from the phase I CRB-402 study of anti-Bcma CAR-T cell therapy Bb21217 in patients with Relapsed and refractory multiple myeloma: correlation of expansion and duration of response with T cell phenotypes","volume":"136","author":"Alsina","year":"2020","journal-title":"Blood"},{"key":"2025100309313490000_11.6.e006699.31","doi-asserted-by":"crossref","DOI":"10.15252\/embj.2020104730","article-title":"Rewired signaling network in T cells expressing the Chimeric antigen receptor (CAR)","volume":"39","author":"Dong","year":"2020","journal-title":"EMBO J"},{"key":"2025100309313490000_11.6.e006699.32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1700939114"},{"key":"2025100309313490000_11.6.e006699.33","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2009.03206.x"},{"key":"2025100309313490000_11.6.e006699.34","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.2.807"},{"key":"2025100309313490000_11.6.e006699.35","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200318025"},{"key":"2025100309313490000_11.6.e006699.36","doi-asserted-by":"publisher","DOI":"10.1038\/89782"},{"key":"2025100309313490000_11.6.e006699.37","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41375-018-0242-6","article-title":"APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: therapeutic implications","volume":"33","author":"Tai","year":"2019","journal-title":"Leukemia"},{"key":"2025100309313490000_11.6.e006699.38","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1610497"},{"key":"2025100309313490000_11.6.e006699.39","doi-asserted-by":"crossref","DOI":"10.3390\/cells11010021","article-title":"Natural Receptor- and ligand-based Chimeric antigen receptors: strategies using natural ligands and receptors for targeted cell killing","volume":"11","author":"Branella","year":"2021","journal-title":"Cells"},{"key":"2025100309313490000_11.6.e006699.40","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0598-449"},{"key":"2025100309313490000_11.6.e006699.41","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1038\/s41591-021-01436-0","article-title":"CAR T cells with dual targeting of Cd19 and Cd22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial","volume":"27","author":"Spiegel","year":"2021","journal-title":"Nat Med"},{"key":"2025100309313490000_11.6.e006699.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01497-1"},{"key":"2025100309313490000_11.6.e006699.43","unstructured":"Ramakrishnan A . Phase 1 Alexander study of Auto3, the first Cd19\/22 dual targeting CAR T cell therapy, with Pembrolizumab in patients with Relapsed\/refractory (R\/R) DLBCL. 2020. Available: https:\/\/ash.confex.com\/ash\/2020\/webprogram\/Paper133960.html"}],"updated-by":[{"DOI":"10.1136\/jitc-2023-006699corr1","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T00:00:00Z","timestamp":1689033600000}}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2023-006699","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T16:31:44Z","timestamp":1759509104000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2023-006699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6]]},"references-count":43,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,6,30]]},"published-print":{"date-parts":[[2023,6]]}},"alternative-id":["10.1136\/jitc-2023-006699"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2023-006699","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6]]}}}