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Memory-like NK cells armed with a neoepitope-specific CAR exhibit potent activity against NPM1 mutated acute myeloid leukemia.
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2022-06-13 , DOI: 10.1073/pnas.2122379119
Han Dong 1, 2 , James Dongjoo Ham 3, 4 , Guangan Hu 3, 4 , Guozhu Xie 3, 4 , Juliana Vergara 5 , Yong Liang 5 , Alaa Ali 5 , Mubin Tarannum 5 , Hannah Donner 3, 4 , Joanna Baginska 6 , Yasmin Abdulhamid 5 , Khanhlinh Dinh 5 , Robert J Soiffer 5 , Jerome Ritz 5 , Laurie H Glimcher 1, 2 , Jianzhu Chen 3, 4 , Rizwan Romee 5
Affiliation  

Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immune-based therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical trials in patients with relapsed/refractory AML. Here, we show that arming CIML NK cells with a neoepitope-specific chimeric antigen receptor (CAR) significantly enhances their antitumor responses to nucleophosphmin-1 (NPM1)-mutated AML while avoiding off-target toxicity. CIML NK cells differentiated from peripheral blood NK cells were efficiently transduced to express a TCR-like CAR that specifically recognizes a neoepitope derived from the cytosolic oncogenic NPM1-mutated protein presented by HLA-A2. These CAR CIML NK cells displayed enhanced activity against NPM1-mutated AML cell lines and patient-derived leukemic blast cells. CAR CIML NK cells persisted in vivo and significantly improved AML outcomes in xenograft models. Single-cell RNA sequencing and mass cytometry analyses identified up-regulation of cell proliferation, protein folding, immune responses, and major metabolic pathways in CAR-transduced CIML NK cells, resulting in tumor-specific, CAR-dependent activation and function in response to AML target cells. Thus, efficient arming of CIML NK cells with an NPM1-mutation-specific TCR-like CAR substantially improves their innate antitumor responses against an otherwise intracellular mutant protein. These preclinical findings justify evaluating this approach in clinical trials in HLA-A2+ AML patients with NPM1c mutations.

中文翻译:


配备新表位特异性 CAR 的记忆样 NK 细胞对 NPM1 突变的急性髓系白血病表现出有效的活性。



急性髓系白血病(AML)仍然是一个治疗挑战,肿瘤特异性靶点的缺乏极大地阻碍了有效的免疫疗法的开发。最近的范式改变研究表明,自然杀伤 (NK) 细胞在 IL-12 和 IL-18 短暂激活后表现出先天记忆,导致细胞因子诱导的记忆样 (CIML) NK 细胞分化。 CIML NK 细胞具有增强的抗肿瘤活性,并在复发/难治性 AML 患者的早期临床试验中显示出有希望的结果。在这里,我们证明,用新表位特异性嵌合抗原受体(CAR)武装 CIML NK 细胞可显着增强其对核磷蛋白-1(NPM1)突变的 AML 的抗肿瘤反应,同时避免脱靶毒性。从外周血 NK 细胞分化而来的 CIML NK 细胞被有效转导,表达 TCR 样 CAR,该 CAR 特异性识别源自 HLA-A2 呈递的胞浆致癌 NPM1 突变蛋白的新表位。这些 CAR CIML NK 细胞对 NPM1 突变的 AML 细胞系和患者来源的白血病母细胞表现出增强的活性。 CAR CIML NK 细胞在体内持续存在,并显着改善异种移植模型中的 AML 结局。单细胞 RNA 测序和质谱流式分析确定了 CAR 转导的 CIML NK 细胞中细胞增殖、蛋白质折叠、免疫反应和主要代谢途径的上调,从而导致肿瘤特异性、CAR 依赖性激活和功能响应AML 靶细胞。因此,用 NPM1 突变特异性 TCR 样 CAR 有效武装 CIML NK 细胞可显着改善其针对细胞内突变蛋白的先天抗肿瘤反应。 这些临床前研究结果证明在具有 NPM1c 突变的 HLA-A2+ AML 患者的临床试验中评估这种方法是合理的。
更新日期:2022-06-13
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