Allogeneic natural killer (NK) cell adoptive transfer is a promising treatment for several cancers but is less effective for the treatment of multiple myeloma. In this study, we report on quadruple gene-engineered induced pluripotent stem cell (iPSC)-derived NK cells designed for mass production from a renewable source and for dual targeting against multiple myeloma through the introduction of an NK cell-optimized chimeric antigen receptor (CAR) specific for B cell maturation antigen (BCMA) and a high affinity, non-cleavable CD16 to augment antibody-dependent cellular cytotoxicity when combined with therapeutic anti-CD38 antibodies. Additionally, these cells express a membrane-bound interleukin-15 fusion molecule to enhance function and persistence along with knock out of CD38 to prevent antibody-mediated fratricide and enhance NK cell metabolic fitness. In various preclinical models, including xenogeneic adoptive transfer models, quadruple gene-engineered NK cells consistently demonstrate durable antitumor activity independent of exogenous cytokine support. Results presented here support clinical translation of this off-the-shelf strategy for effective treatment of multiple myeloma.

同种异体自然杀伤 (NK) 细胞过继转移是治疗多种癌症的一种有前景的治疗方法，但对于治疗多发性骨髓瘤效果较差。在这项研究中，我们报告了四重基因工程诱导多能干细胞 (iPSC) 衍生的 NK 细胞，该细胞旨在通过可再生来源进行大规模生产，并通过引入 NK 细胞优化的嵌合抗原受体来双重靶向多发性骨髓瘤。 CAR）特异性针对 B 细胞成熟抗原 (BCMA) 和高亲和力、不可切割的 CD16，与治疗性抗 CD38 抗体联合使用时可增强抗体依赖性细胞毒性。此外，这些细胞表达膜结合的白细胞介素 15 融合分子，以增强功能和持久性，同时敲除CD38 ，以防止抗体介导的自相残杀并增强 NK 细胞的代谢适应性。在各种临床前模型中，包括异种过继转移模型，四重基因工程 NK 细胞始终表现出持久的抗肿瘤活性，不依赖于外源细胞因子的支持。这里提出的结果支持这种现成策略的临床转化，以有效治疗多发性骨髓瘤。