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

Abstract

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.

• Authors: 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, Mirjam H M Heemskerk
• Journal: Blood (Blood) Vol. 129 Issue 10 Pg. 1284-1295 (03 09 2017) ISSN: 1528-0020 [Electronic] United States
• PMID: 28053195 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 by The American Society of Hematology.

Chemical References

• POU2AF1 protein, human
• Receptors, Antigen, T-Cell
• Trans-Activators

Topics

• 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