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

• Published in: Blood 2017-03, Vol.129 (10), p.1284-1295
• Main Authors: Jahn, Lorenz, Hombrink, Pleun, Hagedoorn, Renate S., Kester, Michel G.D., van der Steen, Dirk M., Rodriguez, Tania, Pentcheva-Hoang, Tsvetelina, de Ru, Arnoud H., Schoonakker, Marjolein P., Meeuwsen, Miranda H., Griffioen, Marieke, van Veelen, Peter A., Falkenburg, J.H.Frederik, Heemskerk, Mirjam H.M.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Flow Cytometry; Genetic Engineering - methods; Humans; Immunotherapy, Adoptive - methods; Lymphoma, Non-Hodgkin - immunology; Mice; Multiple Myeloma - immunology; Receptors, Antigen, T-Cell - immunology; T-Lymphocytes - immunology; Trans-Activators - antagonists & inhibitors; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2016-09-737536

Immunotherapy for 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 hamper 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, mantle 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 toward a broad panel of BOB1− but HLA-B*07:02+ 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 with B-cell malignancies, including multiple myeloma. •Isolation and characterization of a high-affinity TCR 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.