Agnese Fiori, Karin Zimmermann, Anna Li, Jörg Westermann, Ioannis Anagnostopoulos, Lutz Menzel, Mario Bunse, Henry Erdlei, Jeyan Jayarajan, Florian Grünschläger, Juan Pablo Ortiz-Aguirre, Simon Haas, Uwe-Jens Teßmann, Jens Freitag, Andreas Rosenwald, Larry W. Kwak, Xiuli Wang, Zhenyuan Dong, Soung-chul Cha, John Reiser, Eigen Peralta, Bahram Valamehr, Jan Krönke, Uta E. Höpken, Armin Rehm
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.