A collaborative effort from The Broad Institute, Heidelberg University, and The University of Calgary has uncovered a mechanism by which T cells in multiple myeloma (MM) patients respond to bispecific T cell engagers (TCEs). The findings, published in Cancer Cell, have found that the clonal expansion of effector CD8⁺ T cells and MHC class I signaling are immunological drivers of TCE therapy. Overall, the research provides valuable insights into the dynamics of the T cell receptor (TCR) repertoire in response to T cell-engaging immunotherapies and highlights potential avenues for future clinical trial designs.

While immunotherapy has shown remarkable success in treating certain cancers, a better understanding of the molecular mechanisms and predictive indicators for treatment response is needed to improve outcomes. The advent of single-cell characterization of pre- and on-treatment biopsies has provided valuable insights, but hematologic malignancies like MM present additional complexities due to heterogeneous immune repertoires and the influence of tumor load and therapy. In this study, the authors sought to perform longitudinal profiling of the bone marrow T cell repertoire and the perturbances created by TCE treatment. The authors also focused on understanding the response of bone marrow-associated T cell repertoire to CD3-targeting immunotherapy, specifically using bispecific antibodies that target tumor cells and CD3 receptors on T cells.  

The researchers analyzed samples from patients with multiple myeloma (MM) receiving BCMAxCD3 bispecific antibody treatment. They performed single-cell characterization of immune cells, transcriptome analysis, and TCR repertoire analysis. The results showed that response to the therapy was associated with clonal expansion of CD8⁺ effector T cells. Patients who responded well to the treatment demonstrated significant clonal expansion in response to the therapy. Conversely, non-responders had an abundance of pre-existing exhausted-like CD8⁺ T cell clones. Additionally, MHC class I:TCR co-signaling was found to amplify the activation of naive T cells by TCEs, promoting their effector differentiation. Furthermore, the loss of MHC class I molecules on malignant plasma cells was identified as a potential mechanism of tumor immune escape, indicating resistance to TCE therapy beyond target antigen loss. In conclusion, the study provided insights into the molecular mechanisms of TCE response in MM patients and highlighted the importance of specific T cell states and MHC class I interactions in influencing the efficacy of immunotherapy.

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. https://doi.org/10.1016/j.ccell.2023.02.008

Tags: bispecific t cell engagers, BiTEs, T cells, T cell