T cell characteristics impact response and resistance to T cell-redirecting bispecific antibodies in multiple myeloma

Abstract Purpose: Bispecific antibodies (BsAbs) directed against B-cell maturation antigen (BCMA; teclistamab) or the orphan G protein-coupled receptor GPRC5D (talquetamab) induce deep and durable responses in heavily pretreated MM patients. However, mechanisms underlying primary and acquired resistance remain poorly understood. Experimental design: The anti-MM activity of teclistamab and talquetamab was evaluated in bone marrow (BM) samples from MM patients. T-cell phenotype and function were assessed in BM/peripheral blood samples obtained from MM patients who were treated with these BsAbs. Results: In ex vivo killing assays with 41 BM samples from BsAb-naïve MM patients, teclistamab- and talquetamab-mediated MM lysis were strongly correlated (r=0.73, P<0.0001). Both BsAbs exhibited poor activity in samples with high regulatory T-cell (Treg) numbers and a low T-cell/MM cell-ratio. Furthermore, comprehensive phenotyping of BM samples derived from patients treated with teclistamab or talquetamab, revealed that high frequencies of PD-1+ CD4+ T-cells, CTLA4+ CD4+ T-cells, and CD38+ CD4+ T-cells were associated with primary resistance. Although this lack of response was linked to modest increase in expression of inhibitory receptors, increasing T-cell/MM cell-ratios by adding extra T-cells enhanced sensitivity to BsAbs. Further, treatment with BsAbs resulted in an increased proportion of T-cells expressing exhaustion markers (PD-1, TIGIT, and TIM-3), which was accompanied by reduced T-cell proliferative potential and cytokine secretion, as well as impaired anti-tumor efficacy in ex vivo experiments. Conclusions: Primary resistance is characterized by a low T-cell/MM cell-ratio and Treg-driven immunosuppression, while reduced T-cell fitness due to continuous BsAb-mediated T-cell activation may contribute to development of acquired resistance.