Chimeric antigen receptor T cells against the IGHV4-34 B cell receptor specifically eliminate neoplastic and autoimmune B cells
Ivan Cohen, Audrey Bochi-Layec, Jean Lemoine, Scott A. Jenks, Pedram Bayat, Ki Hyun Kim, Huiwu Zhao, Ositadimma Ugwuanyi, Federico Stella, Guido Ghilardi, Giulia Gabrielli, Sarah McCuaig, Anastasia Iatrou, Elisavet Vlachonikola, Maria Karipidou, Eleni Bouziani, David Espie, Ranjani Ramasubramanian, Andreas Agathangelidis, Aditya Bhosale, Luca Paruzzo, Giovanni Medico, Brontë Kolar, Regina Bugrovsky, Puneeth Guruprasad, Li-Ping Wang, Jaryse Harris, Evgeny Arons, Yunlin Zhang, Raymone Pajarillo, Portia A. Kreiger, Chi‐Ping Day, S. Cenk Sahinalp, Chih Hao Wu, Alessia Santi, Bria Fulmer, Marcos Cases, Matthew B. Palmer, Patrizia Porazzi, E. John Wherry, RJ Kreitman, Enrico Tiacci, Sokratis A. Apostolidis, Edward M. Behrens, Vijay Bhoj, Igñacio Sanz, Giorgio Inghirami, S. Schuster, Paolo Ghia, Kostas Stamatopoulos, Marco Antonio Ruella
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 IGHV4-34 are highly enriched in B cell malignancies compared with normal B cells. Further, self-reactive IGHV4-34 + 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 + malignant B cells. In addition, although CD19 was down-regulated upon relapse after treatment with CART19, IGHV4-34 + BcR levels remained intact upon relapse after treatment with CART4-34, suggesting reduced risk of antigen-negative escape. In IGHV4-34 + 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 + SLE B cells and deplete IGHV4-34 + 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.