title: 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.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Lorenz
authors.identifier: 0000-0002-9880-7026
authors.initials: L
authors.lastname: Jahn
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Hematopoiesis, Sanquin Research, Amsterdam, The Netherlands.
authors.forename: Pleun
authors.initials: P
authors.lastname: Hombrink
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Renate S
authors.initials: RS
authors.lastname: Hagedoorn
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: van der Steen
authors.affiliation: Research and Development, Bellicum Pharmaceuticals, Inc., Houston, TX.
authors.forename: Tania
authors.initials: T
authors.lastname: Rodriguez
authors.affiliation: Research and Development, Bellicum Pharmaceuticals, Inc., Houston, TX.
authors.forename: Tsvetelina
authors.initials: T
authors.lastname: Pentcheva-Hoang
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Arnoud H
authors.initials: AH
authors.lastname: de Ru
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marjolein P
authors.initials: MP
authors.lastname: Schoonakker
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Miranda H
authors.initials: MH
authors.lastname: Meeuwsen
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Griffioen
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Mirjam H M
authors.initials: MH
authors.lastname: Heemskerk
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D005818:Genetic Engineering / Q000379:methods; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology*; D051379:Mice; D009101:Multiple Myeloma / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C091546:POU2AF1 protein, human; D011948:Receptors, Antigen, T-Cell; D015534:Trans-Activators