Clinical-Grade Armored BCMA CAR-T Cells Overcome TGF-β–Mediated Immunosuppression in Multiple Myeloma

• BCMA CAR T cells are effective in MM, but patients relapse due to TGF-β–driven immunosuppression in the bone marrow microenvironment. • To overcome this, we have developed armored BCMA CAR T cells that exhibit durable anti-tumor activity in preclinical MM models. B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy has shown promise in treating multiple myeloma (MM); however, relapse remains a significant challenge due to the immunosuppressive tumor microenvironment (TME) driven by Transforming Growth Factor-β (TGF-β) present in the bone marrow. To overcome this, we engineered BCMA CAR T cells armored to resist TGF-β suppression by co-expressing a dominant-negative TGF-β receptor II (DNTGF-βRII). Armored BCMA CAR T cells were manufactured with IL-7/IL-15 on the clinically compatible CliniMACS Prodigy® (Miltenyi Biotec) platform, yielding consistent transduction efficiency, expansion, and products that met all release criteria for patient dosing and infusion. The armored BCMA CAR T cells showed reduced pSmad2/3 signaling and T cell exhaustion upon TGF-β1 exposure, indicating successful resistance to TGF-β-mediated suppression, and the cells demonstrated strong cytotoxicity against primary MM tumor cells with prior BCMA exposure. In tumor models, armored BCMA CAR T cells successfully decreased or eliminated tumor burden, increased survival, and persisted in vivo. Additionally, armored BCMA CAR T-treated NSG mice showed no tumor presence after rechallenging with MM tumor cells. In summary, clinically manufactured armored BCMA CAR T cells effectively resist TGF-β-mediated immunosuppression, leading to potent anti-tumor activity in pre-clinical MM tumor models and providing supportive evidence of potential therapeutic benefit.