Abstract
Multiple myeloma (MM) is a hematological cancer caused by abnormal proliferation of plasma cells in the bone marrow, and novel types of treatment are needed for this deadly disease. In this study, we aimed to develop novel CS1 CAR-T cells and bispecific CS1-BCMA CAR-T cells to specifically target multiple myeloma. We generated a new CS1 (CD319, SLAM-7) antibody, clone (7A8D5), which specifically recognized the CS1 antigen, and we applied it for the generation of CS1-CAR. CS1-CAR-T cells caused specific killing of CHO-CS1 target cells with secretion of IFN-gamma and targeted multiple myeloma cells. In addition, bispecific CS1-BCMA-41BB-CD3 CAR-T cells effectively killed CHO-CS1 and CHO-BCMA target cells, killed CS1/BCMA-positive multiple myeloma cells, and secreted IFN-gamma. Moreover, CS1-CAR-T cells and bispecific CS1-BCMA CAR-T cells effectively blocked MM1S multiple myeloma tumor growth in vivo. These data for the first time demonstrate that novel CS1 and bispecific CS1-BCMA-CAR-T cells are effective in targeting MM cells and provide a basis for future clinical trials.
Highlights
Cellular immunotherapy is an emerging and highly promising approach for the treatment of cancer
One of the challenges is that BCMA can be downregulated or lost, causing resistance to this treatment; novel CAR-T cells and bi-specific CAR-T cells need to be developed for effective therapy of multiple myeloma to bispecific CD19
We developed hybridoma clones against the extracellular domain of CS1 and selected the best clone that bound to CS1 antigen
Summary
Cellular immunotherapy is an emerging and highly promising approach for the treatment of cancer. CAR-T cells targeting tumor-associated antigens (TAA) can be infused into patients (called adoptive cell transfer or ACT), representing an efficient immunotherapy approach [9,10,11,12,13,14]. CS1 (SLAM family member 7, CD319) and BCMA (tumor necrosis factor receptor superfamily member 17) proteins are often overexpressed in multiple myeloma [15,16,17,18,19]. Based on their high percentage of expression in multiple myeloma, both targets are used for CAR-T cell therapy [19,20,21,22]. One of the challenges is that BCMA can be downregulated or lost, causing resistance to this treatment; novel CAR-T cells and bi-specific CAR-T cells need to be developed for effective therapy of multiple myeloma to bispecific CD19–
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