Chimeric antigen receptor T cells against the IGHV4-34 B cell receptor specifically eliminate neoplastic and autoimmune B cells

Current US Food and Drug Administration-approved 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 <i>IGHV4-34</i> are highly enriched in B cell malignancies compared with normal B cells. Further, self-reactive IGHV4-34<sup>+</sup> 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<sup>+</sup> malignant B cells. In addition, although CD19 was down-regulated upon relapse after treatment with CART19, IGHV4-34<sup>+</sup> BcR levels remained intact upon relapse after treatment with CART4-34, suggesting reduced risk of antigen-negative escape. In IGHV4-34<sup>+</sup> HBL1 cell line-derived 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<sup>+</sup> SLE B cells and deplete IGHV4-34<sup>+</sup> 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.

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Publication Details

Journal
Science Translational Medicine
Published
2026-02-04
DOI
https://doi.org/10.1126/scitranslmed.adr9382
Citations
1
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
24.20
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article

Chimeric antigen receptor T cells against the IGHV4-34 B cell receptor specifically eliminate neoplastic and autoimmune B cells

Chi‐Ping Day, Eleni Bouziani, Bria Fulmer, Vijay Bhoj et al.
1 citations
Science Translational Medicine
CAR-T cell therapy research
24.20
article

Chimeric antigen receptor T cells against the IGHV4-34 B cell receptor specifically eliminate neoplastic and autoimmune B cells

Chi‐Ping Day, Eleni Bouziani, Bria Fulmer, Vijay Bhoj, S. Schuster, Ki H. Kim, Elisavet Vlachonikola, Alessia Santi, Anastasia Iatrou, Giulia Gabrielli, Jaryse Harris, Chih Hao Wu, Puneeth Guruprasad, Scott A. Jenks, David Espie, Regina Bugrovsky, Jean Lemoine, Marcos Cases, Marco Antonio Ruella, Brontë Kolar, Evgeny Arons, Maria Karipidou, Igñacio Sanz, Federico Stella, Sokratis A. Apostolidis, Portia A. Kreiger, Audrey Bochi-Layec, Ranjani Ramasubramanian, Yunlin Zhang, RJ Kreitman, Ivan Cohen, Huiwu Zhao, Giovanni Medico, Ositadimma Ugwuanyi, Luca Paruzzo, Sarah McCuaig, Paolo Ghia, Guido Ghilardi, Raymone Pajarillo, Matthew B. Palmer, Giorgio Inghirami, Pedram Bayat, Aditya Bhosale, Kostas Stamatopoulos, S. Cenk Sahinalp, Edward M. Behrens, Li-Ping Wang, Enrico Tiacci, E. John Wherry, Andreas Agathangelidis, Patrizia Porazzi
article en
1 citations

Abstract

Current US Food and Drug Administration-approved 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 <i>IGHV4-34</i> are highly enriched in B cell malignancies compared with normal B cells. Further, self-reactive IGHV4-34<sup>+</sup> 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<sup>+</sup> malignant B cells. In addition, although CD19 was down-regulated upon relapse after treatment with CART19, IGHV4-34<sup>+</sup> BcR levels remained intact upon relapse after treatment with CART4-34, suggesting reduced risk of antigen-negative escape. In IGHV4-34<sup>+</sup> HBL1 cell line-derived 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<sup>+</sup> SLE B cells and deplete IGHV4-34<sup>+</sup> 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.

Science Translational MedicineVol. 18(835)
National Institutes of Health (US), Children's Hospital of Philadelphia (US), Emory University (US), Vita-Salute San Raffaele University (IT), National and Kapodistrian University of Athens (GR), Cornell University (US), University of Perugia (IT), Hospital of the University of Pennsylvania (US), Pennsylvania Hospital (US), Presbyterian Hospital (US), UPMC Hillman Cancer Center (US), IRCCS Ospedale San Raffaele (IT), Centre for Research and Technology Hellas (GR), National Cancer Institute (US), Center for Cancer Research (US), University of Pennsylvania (US)
Good health and well-being
Openalex Percentile: Top 1%
CAR-T cell therapy research
24.20
DOISourceOpenAlex
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