{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:35:45Z","timestamp":1792798545274,"version":"4.5.0"},"reference-count":71,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"835","funder":[{"DOI":"10.13039\/100001219","name":"Lymphoma Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001219","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100003837","name":"Hairy Cell Leukemia Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005189","name":"Leukemia and Lymphoma Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005189","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012728","name":"Frederick National Laboratory for Cancer Research","doi-asserted-by":"publisher","award":["75N91019D00024"],"award-info":[{"award-number":["75N91019D00024"]}],"id":[{"id":"10.13039\/100012728","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020717","name":"Center for High Performance Computing, Shanghai Jiao Tong University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100020717","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["21198"],"award-info":[{"award-number":["21198"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020046","name":"DKMS Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020046","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006351","name":"Colton Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006351","id-type":"DOI","asserted-by":"publisher"}]},{"name":"LLS","award":["SCOR-22915-22"],"award-info":[{"award-number":["SCOR-22915-22"]}]},{"name":"Emory Autoimmunity Center of Excellence","award":["2U19AI110483-11"],"award-info":[{"award-number":["2U19AI110483-11"]}],"id":[{"id":"https:\/\/ror.org\/02y9qjz38","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,2,4]]},"abstract":"<jats:p>\n                    Current US Food and Drug Administration\u2013approved chimeric antigen receptor (CAR) T cell therapies for B cell leukemias and lymphomas target CD19, which is widely expressed across the B cell lineage, often leading to on-target, off-tumor B cell depletion, prolonged immune suppression, and antigen-negative escape in a subset of patients. In contrast, B cell receptor (BcR) signaling is essential for the survival of most mature B cell neoplasms, and BcRs carrying the immunoglobulin heavy variable gene\n                    <jats:italic toggle=\"yes\">IGHV4-34<\/jats:italic>\n                    are highly enriched in B cell malignancies compared with normal B cells. Further, self-reactive IGHV4-34\n                    <jats:sup>+<\/jats:sup>\n                    serum autoantibodies are enriched in aggressive systemic lupus erythematosus (SLE) and other autoimmune diseases. Here, we developed CAR T cells targeting the BcR carrying IGHV4-34 (CART4-34). We found that CART4-34 showed specific cytotoxicity and cytokine secretion toward IGHV4-34\n                    <jats:sup>+<\/jats:sup>\n                    malignant B cells. In addition, although CD19 was down-regulated upon relapse after treatment with CART19, IGHV4-34\n                    <jats:sup>+<\/jats:sup>\n                    BcR levels remained intact upon relapse after treatment with CART4-34, suggesting reduced risk of antigen-negative escape. In IGHV4-34\n                    <jats:sup>+<\/jats:sup>\n                    HBL1 cell line\u2013derived xenograft mouse models, CART4-34 showed robust expansion and antitumor activity comparable to those of CART19. Optimized CAR:BcR binding using shorter CAR hinge domains improved immune synapse morphology and in vivo activity. In addition, we showed that CART4-34 could target human IGHV4-34\n                    <jats:sup>+<\/jats:sup>\n                    SLE B cells and deplete IGHV4-34\n                    <jats:sup>+<\/jats:sup>\n                    autoantibodies ex vivo, without targeting healthy B cells or affecting total IgG titers. In conclusion, we developed a CAR T cell product that specifically targets pathogenic B cells in lymphoid malignancies and SLE, offering potential for precision cell therapy for these indications.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adr9382","type":"journal-article","created":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T18:58:12Z","timestamp":1770231492000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":18,"title":["Chimeric antigen receptor T cells against the IGHV4-34 B cell receptor specifically eliminate neoplastic and autoimmune B cells"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9085-7642","authenticated-orcid":true,"given":"Ivan J.","family":"Cohen","sequence":"first","affiliation":[{"name":"Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Medicine, Division of Hematology\/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2858-9986","authenticated-orcid":true,"given":"Audrey C.","family":"Bochi-Layec","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Medicine, Division of Hematology\/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5833-6728","authenticated-orcid":true,"given":"Jean","family":"Lemoine","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Medicine, Division of Hematology\/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7485-8331","authenticated-orcid":true,"given":"Scott","family":"Jenks","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Rheumatology, School of Medicine, Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8166-1904","authenticated-orcid":true,"given":"Pedram","family":"Bayat","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Medicine, Division of Hematology\/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8835-7511","authenticated-orcid":true,"given":"Ki Hyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Medicine, Division of Hematology\/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1617-2209","authenticated-orcid":true,"given":"Huiwu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Surgery, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ositadimma","family":"Ugwuanyi","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Medicine, Division of Hematology\/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3401-1309","authenticated-orcid":true,"given":"Federico","family":"Stella","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Medicine, Division of Hematology\/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0095-3579","authenticated-orcid":true,"given":"Guido","family":"Ghilardi","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Medicine, Division of Hematology\/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1162-8712","authenticated-orcid":true,"given":"Giulia","family":"Gabrielli","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Medicine, Division of Hematology\/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2304-7739","authenticated-orcid":true,"given":"Sarah","family":"McCuaig","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Iatrou","sequence":"additional","affiliation":[{"name":"Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisavet","family":"Vlachonikola","sequence":"additional","affiliation":[{"name":"Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4729-2607","authenticated-orcid":true,"given":"Maria","family":"Karipidou","sequence":"additional","affiliation":[{"name":"Institute of Applied Biosciences, Centre for Research and Technology Hellas, Thessaloniki 57001, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7129-5123","authenticated-orcid":true,"given":"Eleni","family":"Bouziani","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9074-6511","authenticated-orcid":true,"given":"David","family":"Espie","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA."},{"name":"Department of Medicine, Division of Hematology\/Oncology, Hospital of University of Pennsylvania, Philadelphia, PA 19104, 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