Bispecific BAFF-R/BCMA CAR T cells control growth of heterogeneous plasma cells in multiple myeloma
Multiple myeloma treatment has experienced tremendous advances through chimeric antigen receptor (CAR) therapies directed to the B cell maturation antigen (BCMA), but remissions are usually transient. To mitigate the risk of BCMA immune escape, we aimed for a simultaneous targeting of BCMA together with the B cell-activating factor receptor (BAFF-R). Single-cell RNA sequencing discovered increased BAFF-R gene (TNFRSF13C) expression in relapsed and refractory multiple myeloma cases, and it emerged as prognostic marker for long-term complete responses. BAFF-R was expressed in plasma cells at earlier maturation stages compared with BCMA-positive plasma cell phenotypes. Bispecific BAFF-R/BCMA CARs endowed T cells with cytolytic efficacy against multiple myeloma cell lines and primary multiple myeloma cells. In vivo, the dual CAR compensated for BCMA downregulation when BAFF-R was expressed, preventing the evolution of antigen escape mutants that drive resistance to CAR T cell therapy. Our study proposes BAFF-R as a complementary target antigen suitable to eliminate malignant plasma cells with less advanced differentiation, lack of BCMA, and occurrence in dismal prognosis patients.
Authors
- Jens Freitag
- John Reiser (ORCID: https://orcid.org/0000-0002-6864-166X)
- Lutz Menzel (ORCID: https://orcid.org/0000-0002-3816-6255)
- Jeyan Jayarajan
- Jan Krönke (ORCID: https://orcid.org/0000-0002-4649-0506)
- Simon Haas (ORCID: https://orcid.org/0000-0001-9227-2051)
- Xiuli Wang (ORCID: https://orcid.org/0000-0001-5964-4327)
- Florian Grünschläger (ORCID: https://orcid.org/0000-0003-0021-6912)
- Karin Zimmermann (ORCID: https://orcid.org/0000-0002-6718-265X)
- Andreas Rosenwald
- Mario Bunse (ORCID: https://orcid.org/0000-0002-7554-2520)
- Bahram Valamehr (ORCID: https://orcid.org/0000-0002-5917-3585)
- Uta E. Höpken (ORCID: https://orcid.org/0000-0002-0776-4893)
- Larry W. Kwak (ORCID: https://orcid.org/0000-0002-1884-5349)
- Ioannis Anagnostopoulos (ORCID: https://orcid.org/0000-0002-4077-0822)
- Armin Rehm (ORCID: https://orcid.org/0000-0001-7490-1950)
- Eigen Peralta
- Henry Erdlei
- Agnese Fiori
- Zhenyuan Dong (ORCID: https://orcid.org/0000-0003-2924-8088)
- Anna Li (ORCID: https://orcid.org/0000-0002-4702-7783)
- Soung-chul Cha
- Jörg Westermann
- Juan Pablo Ortiz-Aguirre
- Uwe-Jens Teßmann
Institutions
- Max Delbrück Center (DE)
- Heidelberg University (DE)
- University of Würzburg (DE)
- City of Hope (US)
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE)
- Fate Therapeutics (United States) (US)
- Helios Hospital Berlin-Buch (DE)
- Franklin University (US)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Molecular Therapy
- Published
- 2025-12-09
- DOI
- https://doi.org/10.1016/j.ymthe.2025.12.005
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Julius-Maximilians-Universität Würzburg