Friedrich et al. performed longitudinal T cell analysis along with TCR clonotyping on the peripheral blood and bone marrow of patients with MM in response to bispecific T cell engagers (TCEs). The clonal expansion of the pre-existing T cell repertoire determined the response to TCEs in MM, with increases in effector (CD8+CX3CR1+) T cell clones associated with responders, and increases in exhausted-like T cell clones associated with non-responders. MHC-I-dependent priming of naive T cells amplified TCE-mediated CD8+ T cell activation, whereas loss of TCE target antigen or MHC-I blockade reduced clonal expansion in all effector cell subsets.
Contributed by Shishir Pant
ABSTRACT: 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.