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

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.