Enhancing T cell cytotoxicity in multiple myeloma with bispecific αPD-L1 × αCD3 T cell engager-armed T cells and low-dose bortezomib therapy.

Abstract

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by frequent relapse due to acquired treatment resistance, underscoring the need for innovative therapies, particularly for relapsed cases. This study explores the effects of low-dose bortezomib (BTZ) on programmed death ligand 1 (PD-L1) expression in MM cell lines and its potential to enhance T cell-mediated anti-tumor responses. Utilizing this PD-L1 upregulation, we employed bispecific αPD-L1 × αCD3 T cell engager-armed T cells (BATs) to block PD-L1 signaling and activate T cells. Flow cytometry confirmed that BATs selectively bound CD3 on T cells and PD-L1 on cancer cells, inducing T cell activation and proliferation without directly affecting cancer cell viability. BATs' cytotoxic activity was evaluated in MM cell lines with or without BTZ-induced PD-L1 expression. While KMS-12-PE cells showed no significant response, BATs significantly increased cell death in L363 cells, with further enhancement by BTZ. In RPMI-8226 cells, BATs demonstrated robust cytotoxicity, further amplified by BTZ. These results suggest that BATs, particularly in combination with BTZ, represent a promising strategy for treating MM, including bortezomib-resistant cases.