Chimeric antigen receptor T cells against the IGHV4-34 B cell receptor specifically eliminate neoplastic and autoimmune B cells
Ivan J. Cohen*, Audrey C. Bochi-Layec*, Jean Lemoine*, Scott Jenks, Pedram B Bayat, and 46 more authors
Science Translational Medicine, 2026
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. CAR T cells against the IGHV4-34 B cell receptor specifically target pathogenic B cells in both lymphoproliferative neoplasms and lupus. Chimeric antigen receptor (CAR) T cell therapies for B cell malignancies currently target CD19; however, CD19 is widely expressed across the B cell lineage, resulting in killing of nonmalignant B cells and prolonged immune suppression, and some patients develop antigen-negative escape. Here, Cohen and colleagues showed that the immunoglobulin heavy-chain variable gene IGHV4-34 is expressed in a substantial portion of B cell malignancies and then developed and optimized CAR T cells targeting B cell receptors carrying IGHV4-34 (CART4-34). In mice, optimized CART4-34 demonstrated similar efficacy to CAR T cells against CD19, with in vitro data supporting preservation of nonmalignant B cells and reduced risk of antigen-negative escape. CART4-34 also targeted pathogenic B cells from patients with systemic lupus erythematosus (SLE) without affecting the overall B cell population, altogether highlighting the potential of CART4-34 therapy for patients suffering from IGHV4-34+ malignancies and SLE. —Melissa L. Norton
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