The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients

Bispecific T cell engagers (TCEs) have shown promise in the treatment of various cancers, but the immunological mechanism and molecular determinants of primary and acquired resistance to TCEs remain poorly understood. Here, we identify conserved behaviors of bone marrow-residing T cells in multiple myeloma patients undergoing BCMAxCD3 TCE therapy. We show that the immune repertoire reacts to TCE therapy with cell state-dependent clonal expansion and find evidence supporting the coupling of tumor recognition via major histocompatibility complex class I (MHC class I), exhaustion, and clinical response. We find the abundance of exhausted-like CD8+ T cell clones to be associated with clinical response failure, and we describe loss of target epitope and MHC class I as tumor-intrinsic adaptations to TCEs. These findings advance our understanding of the in vivo mechanism of TCE treatment in humans and provide the rationale for predictive immune-monitoring and conditioning of the immune repertoire to guide future immunotherapy in hematological malignancies. [Display omitted] •Single-cell TCR tracing identifies conserved T cell responses to TCEs in humans•Clonal expansion of effector CD8+ T cells is an immunological driver of TCE therapy•Naive T cells require additional MHC class I signal and differentiate upon TCE activation•The abundance of exhausted CD8+ clones predicts response failure in multiple myeloma Bispecific T cell engagers (TCEs) have shown promise in the treatment of various cancers, but their mode of action in humans is elusive. Providing new insight into immunological mechanisms, Friedrich et al. identify how T cells in multiple myeloma patients respond to TCEs according to their cell state and link inter-individual differences in the immune repertoire to clinical response.