{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T17:59:09Z","timestamp":1780768749782,"version":"3.54.1"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":146,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100032351","name":"Leucid Bio","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100032351","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Second-generation CAR T-cells have transformed the management of B-cell malignancy. However, in vivo functional persistence is often limited, highlighting a key mechanism of treatment failure. We have engineered a parallel (p)CAR platform that delivers dual CD28 and 4-1BB co-stimulation via a co-expressed CAR and chimeric co-stimulatory receptor (CCR). To target CD19, we employed an avidity-optimized FMC63 scFv to direct CAR specificity while utilizing an unmodified FMC63 scFv to target the CCR. Here, we describe the late-stage optimization of this system for Phase 1 clinical evaluation. First, we confirmed that the avidity-optimized scFv lacked off-target specificity. To minimize risk of insertional mutagenesis and immunogenicity, respectively, we transitioned from a gammaretrovirus to a third-generation lentiviral expression vector and removed epitope tags used to discriminate between CAR and CCR expression. Most strikingly, we found that inactivation of immune tyrosine activation motif 2 and 3 within our pCAR prototype markedly potentiated efficacy in xenograft-bearing NSG mice. Mechanistically, this resulted from increased pCAR T-cell functional persistence and organ infiltration, with enhanced local clearance of malignant B-cells. These data set the scene for evaluation of this iteratively honed pCAR candidate in a clinical trial in relapsed\/refractory B-cell non-Hodgkin's lymphoma.<\/jats:p>","DOI":"10.1093\/cei\/uxag032","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T11:44:46Z","timestamp":1779536686000},"source":"Crossref","is-referenced-by-count":0,"title":["Optimization of a parallel CAR for B-cell lymphoma via ITAM attenuation and target specificity validation"],"prefix":"10.1093","volume":"220","author":[{"given":"Fahima","family":"Kausar","sequence":"first","affiliation":[{"name":"Leucid Bio Ltd., Guy\u2019s Hospital , Great Maze Pond, London SE1 9RT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Davis","sequence":"additional","affiliation":[{"name":"Leucid Bio Ltd., Guy\u2019s Hospital , Great Maze Pond, London SE1 9RT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Larcombe-Young","sequence":"additional","affiliation":[{"name":"Leucid Bio Ltd., Guy\u2019s Hospital , Great Maze Pond, London SE1 9RT ,","place":["UK"]},{"name":"King\u2019s College London, CAR Mechanics Group, Department of Precision & Population Oncology, School of Cancer and Pharmaceutical Sciences , London SE1 9RT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Bove","sequence":"additional","affiliation":[{"name":"Leucid Bio Ltd., Guy\u2019s Hospital , Great Maze Pond, London SE1 9RT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farzin","family":"Farzaneh","sequence":"additional","affiliation":[{"name":"King\u2019s College London, Department of Haematology, School of Cancer and Pharmaceutical Sciences , London SE5 9RS ,","place":["UK"]},{"name":"ViroCell Biologics, Zayed Centre for Research into Rare Diseases in Children , London WC1N 1DZ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Graham","sequence":"additional","affiliation":[{"name":"King\u2019s College London, Department of Haematology, School of Cancer and Pharmaceutical Sciences , London SE5 9RS ,","place":["UK"]},{"name":"King\u2019s College Hospital, Department of Haematology , London SE5 9RS ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reuben","family":"Benjamin","sequence":"additional","affiliation":[{"name":"King\u2019s College London, Department of Haematology, School of Cancer and Pharmaceutical Sciences , London SE5 9RS ,","place":["UK"]},{"name":"King\u2019s College Hospital, Department of Haematology , London SE5 9RS ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M","family":"Davies","sequence":"additional","affiliation":[{"name":"Leucid Bio Ltd., Guy\u2019s Hospital , Great Maze Pond, London SE1 9RT ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8275-8488","authenticated-orcid":false,"given":"John","family":"Maher","sequence":"additional","affiliation":[{"name":"Leucid Bio Ltd., Guy\u2019s Hospital , Great Maze Pond, London SE1 9RT ,","place":["UK"]},{"name":"King\u2019s College London, CAR Mechanics Group, Department of Precision & Population Oncology, School of Cancer and Pharmaceutical Sciences , London SE1 9RT ,","place":["UK"]},{"name":"Department of Immunology, Eastbourne Hospital , Kings Drive, Eastbourne, East Sussex BN21 2UD ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"2026060613013865500_uxag032-B1","doi-asserted-by":"crossref","first-page":"2515135520927164","DOI":"10.1177\/2515135520927164","article-title":"CAR T-cell immunotherapy of B-cell malignancy: the story so 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