Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors
Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors
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DOI：
10.1056/nejmoa1910607
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发表时间：
2020-02-06
影响因子：
158.5
通讯作者：
Rezvani, Katayoun
中科院分区：
文献类型：
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作者：
Liu, Enli;Marin, David;Rezvani, Katayoun
背景抗CD19嵌合抗原受体（CAR）T细胞疗法在B细胞癌症中显示出显着的临床疗效。然而，CAR T细胞会引起严重的毒性作用，而且细胞的制造很复杂。经过修饰以表达抗 CD19 CAR 的自然杀伤 (NK) 细胞有可能克服这些限制。方法 在这项 1 期和 2 期试验中，我们向 11 名复发或难治性 CD19 阳性癌症（非霍奇金淋巴瘤或慢性淋巴细胞白血病 [CLL]）患者注射了源自脐带血的 HLA 不匹配抗 CD19 CAR-NK 细胞。 NK 细胞用逆转录病毒载体转导，该载体表达编码抗 CD19 CAR、白细胞介素 15 和诱导型 caspase 9 作为安全开关的基因。这些细胞在体外进行扩增，并在淋巴细胞清除化疗后以三种剂量之一（每公斤体重 1x10(5)、1x10(6) 或 1x10 CAR-NK 细胞）单次输注给药。结果 CAR-NK 细胞的施用与细胞因子释放综合征、神经毒性或移植物抗宿主病的发生无关，并且炎症细胞因子（包括白细胞介素 6）的水平没有高于基线。未达到最大耐受剂量。在 11 名接受治疗的患者中，8 名（73%）有缓解；在这些患者中，7 名（4 名淋巴瘤患者和 3 名 CLL 患者）获得完全缓解，1 名患者的里氏转化部分得到缓解，但患有持续性 CLL。所有剂量水平的输注后 30 天内均出现快速反应。输注的 CAR-NK 细胞扩增并维持在低水平至少 12 个月。结论 在 11 名复发或难治性 CD19 阳性癌症患者中，大多数患者对 CAR-NK 细胞治疗有反应，且未出现重大毒性作用。 （由 M.D. Anderson 癌症中心 CLL 和淋巴瘤 Moonshot 以及美国国立卫生研究院资助；ClinicalTrials.gov 编号：NCT03056339。）
BACKGROUND Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations. METHODS In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19positive cancers (non-Hodgkin's lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1x10(5), 1x10(6), or 1x10 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy. RESULTS The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter's transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months. CONCLUSIONS Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339.)