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| Item Type: | Article |
|---|---|
| Title: | Bispecific BAFF-R/BCMA CAR T cells control growth of heterogeneous plasma cells in multiple myeloma |
| Creators Name: | Fiori, Agnese, Zimmermann, Karin, Li, Anna, Westermann, Jörg, Anagnostopoulos, Ioannis, Menzel, Lutz, Bunse, Mario, Erdlei, Henry, Jayarajan, Jeyan, Grünschläger, Florian, Ortiz-Aguirre, Juan Pablo, Haas, Simon, Teßmann, Uwe-Jens, Freitag, Jens, Rosenwald, Andreas, Kwak, Larry, Wang, Xiuli, Dong, Zhenyuan, Cha, Soungchul, Reiser, John, Peralta, Eigen, Valamehr, Bahram, Krönke, Jan, Höpken, Uta E. and Rehm, Armin |
| Abstract: | 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 to 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. |
| Keywords: | Multiple Myeloma, Immunotherapy, Chimeric Antigen Receptors, Immune Escape, T Cells, B Cells, Maturation Antigen, B Cell Activating Factor Receptor, Antigen Escape, Plasma Cell, Animals, Mice |
| Source: | Molecular Therapy |
| ISSN: | 1525-0016 |
| Publisher: | Elsevier / Cell Press |
| Date: | 9 December 2025 |
| Official Publication: | https://doi.org/10.1016/j.ymthe.2025.12.005 |
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