Initial T-Cell Landscape May Influence Response to Bispecifics in Multiple Myeloma

A recent study suggests the initial T-cell landscape could shape responses to bispecific T-cell engagers (TCEs) in patients with multiple myeloma (MM).

Mirco Friedrich, MD, PhD, of the Heidelberg University Hospital in Germany and the Broad Institute of Massachusetts Institute of Technology and Harvard and colleagues conducted the research.

Dr. Friedrich and colleagues conducted the study because 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.”

They analyzed the transcriptome and T-cell receptor repertoire of bone marrow-associated immune cells in samples from patients with MM who were receiving monotherapy with a TCE targeting BCMA and CD3. The study included samples from seven patients with newly diagnosed MM and samples from 18 patients with relapsed or refractory MM. The researchers also analyzed samples from five healthy bone marrow donors.

They used single-cell T-cell receptor tracing to identify “conserved T cell responses to TCEs” in the bone marrow of patients with MM who were receiving a TCE targeting BCMA and CD3.

Dr. Friedrich and colleagues found the clonal expansion of effector CD8-positive T cells is an “immunological driver” of TCE therapy. Furthermore, the “abundance of exhausted-like CD8-positive T cell clones” was associated with “clinical response failure,” according to the study’s authors. They also described the “loss of target epitope and MHC class I as tumor-intrinsic adaptations to TCEs.”

“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,” Dr. Friedrich and colleagues wrote.

Furthermore, naïve T cells “require additional” MHC class I and “differentiate upon TCE activation,” according to the study’s authors.

“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,” Dr. Friedrich and colleagues concluded.

Reference

Friedrich MJ, Neri P, Kehl N, et al. The pre-existing T cell landscape determines the response to bispecific T cell engagers in multiple myeloma patients. Cancer Cell. 2023;41(4):711-725.e6. doi:10.1016/j.ccell.2023.02.008