Department of Stem Cell Transplantation and Cellular Therapy and.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.
Blood. 2021 Feb 4;137(5):624-636. doi: 10.1182/blood.2020007748.
Immune checkpoint therapy has resulted in remarkable improvements in the outcome for certain cancers. To broaden the clinical impact of checkpoint targeting, we devised a strategy that couples targeting of the cytokine-inducible Src homology 2-containing (CIS) protein, a key negative regulator of interleukin 15 (IL-15) signaling, with fourth-generation "armored" chimeric antigen receptor (CAR) engineering of cord blood-derived natural killer (NK) cells. This combined strategy boosted NK cell effector function through enhancing the Akt/mTORC1 axis and c-MYC signaling, resulting in increased aerobic glycolysis. When tested in a lymphoma mouse model, this combined approach improved NK cell antitumor activity more than either alteration alone, eradicating lymphoma xenografts without signs of any measurable toxicity. We conclude that targeting a cytokine checkpoint further enhances the antitumor activity of IL-15-secreting armored CAR-NK cells by promoting their metabolic fitness and antitumor activity. This combined approach represents a promising milestone in the development of the next generation of NK cells for cancer immunotherapy.
免疫检查点疗法显著改善了某些癌症的预后。为了扩大检查点靶向治疗的临床影响，我们设计了一种策略，将细胞因子诱导的Src 同源 2 结构域（CIS）蛋白的靶向与第四代“装甲”嵌合抗原受体（CAR）工程相结合，该蛋白是白细胞介素 15（IL-15）信号的关键负调节剂，来源于脐带血的自然杀伤（NK）细胞。通过增强 Akt/mTORC1 轴和 c-MYC 信号传导，这种联合策略增强了 NK 细胞的效应功能，导致有氧糖酵解增加。在淋巴瘤小鼠模型中进行测试时，这种联合方法比单独改变任何一种方法都能更有效地提高 NK 细胞的抗肿瘤活性，消除淋巴瘤异种移植物，没有任何可测量毒性的迹象。我们得出结论，靶向细胞因子检查点通过促进其代谢适应性和抗肿瘤活性，进一步增强了分泌白细胞介素 15 的装甲 CAR-NK 细胞的抗肿瘤活性。这种联合方法代表了癌症免疫治疗中下一代 NK 细胞发展的一个有前途的里程碑。
