The Preexisting T Cell Landscape Determines Response to T Cell-Engagers Therapy

Adaptive immunotherapy including bispecific T cell engagers (TCE) has shown promise in the treatment of various cancers, but clinical responses are heterogeneous and often not durable. As response to TCE is suggested to be independent of tumor recognition and T cell state, molecular determinants or mediators of primary and acquired resistance towards TCE remain poorly understood. Here, we identify conserved behaviors of bone marrow residing CD4+ and CD8+ T cells in multiple myeloma patients undergoing TCE therapy. We show that the bone marrow immune landscape reacts to TCE therapy with cell state-dependent clonal T cell expansion and herewith infer coupling of tumor recognition via MHC-I, T cell exhaustion and clinical response. While we find the abundance of exhausted-like memory CD8+ T cell clones to be associated with clinical response failure, we describe loss of target epitope and MHC class I expression as tumor-intrinsic mechanisms of acquired resistance to TCE. Overall design: Bone marrow resident CD3 cells were isolated by magnetic bead separation and analyzed using 10x Genomics 5' scRNA/VDJ sequencing and 3' scRNA. PT* samples: patients treated with anti-BCMA TCE CART_* samples: patients treated with anti-BCMA CAR T PT*_pre samples: prior initiation of therapy time point PT*_late samples: post initiation of therapy time point (Some of the late samples are relapse samples as indicated in the sample titles)