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TCR-based therapy for multiple myeloma and other B-cell malignancies targeting intracellular transcription factor BOB1

Lorenz Jahn, Pleun Hombrink, Renate S. Hagedoorn, Michel G.D. Kester, Dirk M. van der Steen, Tania Rodriguez, Tsvetelina Pentcheva-Hoang, Arnoud H. de Ru, Marjolein P. Schoonakker, Miranda H. Meeuwsen, Marieke Griffioen, Peter A. van Veelen, J.H. Frederik Falkenburg and Mirjam H.M. Heemskerk

Key points

  • Isolation and characterization of a high-affinity T-cell receptor targeting the intracellular B-cell specific transcription factor BOB1.

  • T-cells expressing a BOB1-specific TCR lysed and eradicated primary multiple myeloma and other B-cell malignancies in vitro and in vivo.

Abstract

Immunotherapy of hematological malignancies or solid tumors by administration of monoclonal antibodies or T-cells engineered to express chimeric antigen receptors or T-cell receptors (TCRs) has demonstrated clinical efficacy. However, antigen-loss tumor escape variants and the absence of currently targeted antigens on several malignancies hampers the widespread application of immunotherapy. We have isolated a TCR targeting a peptide of the intracellular B-cell specific transcription factor BOB1 presented in the context of HLA-B*07:02. TCR gene transfer installed BOB1-specificity and reactivity onto recipient T-cells. TCR-transduced T-cells efficiently lysed primary B-cell leukemia, mantel cell lymphoma and multiple myeloma in vitro. We also observed recognition and lysis of healthy BOB1-expressing B-cells. In addition, strong BOB1-specific proliferation could be demonstrated for TCR-modified T-cells upon antigen encounter. Furthermore, clear in vivo antitumor reactivity was observed of BOB1-specific TCR-engineered T-cells in a xenograft mouse model of established multiple myeloma. Absence of reactivity towards a broad panel of BOB1-negative but HLA-B*07:02pos nonhematopoietic and hematopoietic cells indicated no off-target toxicity. Therefore, administration of BOB1-specific TCR-engineered T-cells may provide novel cellular treatment options to patients suffering from B-cell malignancies including multiple myeloma.

  • Submitted September 6, 2016.
  • Accepted December 22, 2016.