To expand the breadth and extent of current multiple myeloma (MM)-specific immunotherapy, we have identified various antigens on CD138+ tumor cells from newly diagnosed MM patients (n = 616) and confirmed B-cell maturation antigen (BCMA) as a key myeloma-associated antigen. The aim of this study is to target the BCMA, which promotes MM cell growth and survival, by generating BCMA-specific memory CD8+ CTL that mediate effective and long-lasting immunity against MM. Here we report the identification of novel engineered peptides specific to BCMA, BCMA72-80 (YLMFLLRKI), and BCMA54-62 (YILWTCLGL), which display improved affinity/stability to HLA-A2 compared to their native peptides and induce highly functional BCMA-specific CTL with increased activation (CD38, CD69) and co-stimulatory (CD40L, OX40, GITR) molecule expression. Importantly, the heteroclitic BCMA72-80 specific CTL demonstrated poly-functional Th1-specific immune activities [IFN-γ/IL-2/TNF-α production, proliferation, cytotoxicity] against MM, which were correlated with expansion of Tetramer+ and memory CD8+ CTL. Additionally, heteroclitic BCMA72-80 specific CTL treated with anti-OX40 (immune agonist) or anti-LAG-3 (checkpoint inhibitor) display increased immune function, mainly by central memory CTL. These results provide the framework for clinical application of heteroclitic BCMA72-80 peptide, alone and in combination with anti-LAG3 and/or anti-OX40 therapy, in vaccination and/or adoptive immunotherapeutic strategies to generate long-lasting anti-tumor immunity in patients with MM or other BCMA expressing tumors.
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The authors acknowledge the Miriam and Sheldon G Adelson Medical Research Foundation. This work was also supported in part by grants from the National Institutes of Health Grants Special Program in Oncology Research Excellence (SPORE) P50 100707, RO1 CA 207237, and RO1 CA 050947. Dr. Kenneth C. Anderson is an American Cancer Society Clinical Research Professor.
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Bae, J., Samur, M., Richardson, P. et al. Selective targeting of multiple myeloma by B cell maturation antigen (BCMA)-specific central memory CD8+ cytotoxic T lymphocytes: immunotherapeutic application in vaccination and adoptive immunotherapy. Leukemia 33, 2208–2226 (2019). https://doi.org/10.1038/s41375-019-0414-z
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