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.

Specific Adoptive Cellular Immunotherapy in Allogeneic Stem Cell Transplantation

“…These findings suggest an alternative way to treat B-cell malignancies with low amounts of CD20 surface expression as a relatively low amount of peptide ligand antigen may be sufficient to stimulate TCR-mediated immune responses [86]. Other potential targets of TCR in the context of hematological malignancies represent BOB1 and the myeloid differentiation antigen myeloperoxidase (MPO) [87,88]. Recently, a TCR directed against a peptide derived from the MPO protein with a promising safety pattern revealed strong immune responses both in vitro and in vivo [88][89][90].…”

T-Cell Receptor–Based Immunotherapy for Hematologic Malignancies

“…A TCR specific for an HLA-B*07:02-restricted BOB1 epitope was identified from the alloreactive repertoire of a healthy individual and transferred into a retroviral vector. 52 The transferred TCR enabled selective recognition and killing of BOB1-positive primary B-cell leukemia, mantle cell lymphoma, and multiple myeloma cells in vitro. Adoptive transfer of BOB1 TCR-transduced CD8 + T cells also controlled tumor outgrowth in an immunodeficient murine xenograft model of established myeloma.…”

Cellular therapy against public neoantigens

“…van der Lee et al generated T cell clones against the two mass spectrometry-validated epitopes (ΔNPM1) predicted to bind HLA-A*02:01. Interestingly, they were unable to generate any ΔNPM1 neoantigen-specific T cell clones from AML patients using their standard approach of peptide/HLA magnetic-activated cell sorting (MACS) preenrichment, followed by single-cell FACS-based cloning (16).…”