Researchers have developed a next-generation chimeric antigen receptor (CAR) T-cell therapy called

CART4-34

that targets the immunoglobulin heavy-chain variable gene IGHV4-34 on B cell receptors. In preclinical mouse models, it destroys cancer cells as effectively as standard CD19-targeted CAR-T therapies but spares most healthy B cells, avoiding broad immune suppression and reducing risks like prolonged infections. The approach also shows promise for selectively treating autoimmune conditions like systemic lupus erythematosus (SLE) by depleting pathogenic B cells and autoantibodies without affecting overall B cell populations. Published February 4, 2026, in Science Translational Medicine, this work addresses major limitations of current CAR-T treatments, including “on-target, off-tumor” toxicity and antigen escape.

Background on CAR-T Cell Therapy

CAR-T therapy engineers a patient’s own T cells to express synthetic receptors that recognize specific antigens on cancer cells, leading to their destruction. CD19-targeted CAR-T therapies (e.g., approved drugs like Kymriah and Yescarta) have revolutionized treatment for B cell leukemias and lymphomas, often achieving deep remissions. However, CD19 is expressed on nearly all B cells, so these therapies cause widespread B cell depletion (B cell aplasia), long-term immune suppression, higher infection risk, and sometimes severe cytokine release syndrome (CRS) or neurotoxicity. Additionally, cancer cells can lose CD19 expression, leading to relapse in some patients.Researchers have sought more selective targets—markers highly expressed on malignant or pathogenic B cells but rare on healthy ones—to improve safety and durability.

The Innovative Approach: Targeting IGHV4-34

The study focuses on IGHV4-34, a specific immunoglobulin heavy-chain variable gene segment. It is overrepresented in certain B cell malignancies (e.g., diffuse large B cell lymphoma, chronic lymphocytic leukemia) and in pathogenic autoantibodies in aggressive SLE, but expressed sparingly in normal B cells.The team engineered

CART4-34

CAR-T cells to recognize B cell receptors (BcRs) carrying IGHV4-34. They optimized the CAR design with shorter hinge domains to improve binding affinity, immune synapse formation, and overall potency.

Key Methods

• CAR Optimization and In Vitro Testing: CART4-34 variants were tested for specific killing and cytokine release (e.g., IFN-γ, TNF-α) against IGHV4-34-positive malignant B cell lines. Ex vivo assays used patient-derived SLE samples to assess selective depletion of pathogenic IGHV4-34+ B cells and autoantibodies.
• In Vivo Mouse Models: Efficacy was evaluated in xenograft models using IGHV4-34-positive human lymphoma cells (e.g., HBL1 line). Mice received CART4-34 infusions, with direct comparisons to standard anti-CD19 CAR-T (CART19). Tumor burden, T cell expansion, persistence, and potential relapse mechanisms were monitored.

Main Results

• Antitumor Efficacy: In mouse models of large B cell lymphoma, CART4-34 showed robust T cell expansion, potent tumor killing, and overall antitumor activity comparable to CART19. It effectively eliminated IGHV4-34-positive cancer cells.
• Reduced Risk of Antigen Escape: Unlike CD19, IGHV4-34 expression remained stable on cancer cells under selective pressure, lowering the chance of antigen-negative relapse.
• Improved Safety Profile: CART4-34 selectively killed IGHV4-34-positive malignant B cells while largely sparing non-IGHV4-34 healthy B cells, preserving broader immune function. In SLE models, it depleted pathogenic IGHV4-34+ autoantibodies ex vivo without significantly altering total B cell counts or normal IgG levels. No major off-target toxicity or excessive systemic inflammation (e.g., severe CRS) was observed in the targeted design.
• Additional Benefits: The therapy demonstrated specific cytokine production only against target cells, supporting a more controlled immune response.

Implications and Future Directions

This targeted strategy could offer a safer alternative for patients with IGHV4-34-positive B cell cancers or certain autoimmune diseases, potentially reducing the need for broad B cell depletion and associated complications. It may expand CAR-T applications beyond oncology into autoimmunity. Next steps include advancing to human clinical trials, optimizing manufacturing, and confirming efficacy/safety in larger models or early-phase studies.The editor’s summary in the journal emphasizes: “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.”

Citations

1. Cohen, I. J. et al. Chimeric antigen receptor T cells against the IGHV4-34 B cell receptor specifically eliminate neoplastic and autoimmune B cells. Science Translational Medicine 18, eadr9382 (2026). https://doi.org/10.1126/scitranslmed.adr9382
2. Fieldhouse, R. Innovative CAR-T therapy destroys cancer cells without dangerous side effects. Nature News (2026). https://www.nature.com/articles/d41586-026-00358-6