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In January 2017 Jahn L. and colleagues from Leiden University Medical Center, The Netherlands published a paper in Blood, describing a pre-clinical study in which TCR gene transfer of BOB1 (intracellular B-cell specific transcription factor) conferred reactivity to recipient T cells and potent in-vivo anti-tumor activity in a mouse model of Multiple Myeloma (MM).
Identification of BOB1 epitopes and isolation of BOB1 reactive T cell clones
In conclusion, a chimeric BOB1-specific TCR clone conferred high anti-tumor reactivity to transduced T cells when tested in an in-vivo mouse xenograft model for established MM, and therefore paves the way for engineered T cells as a future treatment option for MM.
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.
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