CELL INTELLIGENCE · 肿瘤细胞治疗研究

Multiple myeloma (MM) is an aggressive blood cancer arising from plasma cells. B cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell ( -BCMA-CAR-T) immunotherapies currently provide life-saving treatment for MM patients. Unfortunately, the high cost and manufacturing complexity of autologous CAR-T therapy remain important limitations. Novel research is underway to use CAR-expressing natural killer (NK) cells as an allogeneic CAR-T alternative, but studies have yet to evaluate long-term CAR-NK efficacy against MM. In this study, NK cells were isolated, expanded via feeder-cell stimulation, and engineered to express -BCMA-CAR with or without human IL-15 co-expression using lentiviral vectors. In a xenograft model, both -BCMA-CAR and IL-15 expression were required for persistent restriction of MM growth in the blood and bone marrow. Despite near complete and sustained elimination of MM in the bone marrow, long-term assessment of mice treated with -BCMA-CAR-IL15 NK cells revealed the emergence of extramedullary disease (EMD) in the form of BCMA-positive MM plasmacytomas. This study showcases -BCMA-CAR-IL15 NK cell therapy as a potent anti-MM therapeutic, achieving sustained MM elimination from the bone marrow and greatly extending survival. However, -BCMA-CAR-IL15 NK cells appeared ineffective at eliminating extramedullary disease. By demonstrating the strengths and weaknesses of -BCMA-CAR-IL15 cells, we hope this study could help direct the use of such therapies in clinical trials and provide a valuable pre-clinical MM model for studying and developing interventions for aggressive MM-EMD.