嵌合抗原受体修饰的自然杀伤细胞在 CD19 阳性淋巴肿瘤中的应用。
Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors.
机构信息
From the Departments of Stem Cell Transplantation and Cellular Therapy (E.L., D.M., P.B., R.B., L.N.K., B.O., M. Kaplan, V.N., I.K., A.N.C., M.D., C.H., P.K., R.M., Y.N., R.C., E.J.S., K.R.), Nuclear Medicine (H.A.M.), Leukemia (P. Thompson, W.W., M. Keating), Biostatistics (P. Thall), Laboratory Medicine (K.C.), Hematopathology (E.N.C.), and Lymphoma and Myeloma (S.N., M.W.), University of Texas M.D. Anderson Cancer Center, Houston.
出版信息
N Engl J Med. 2020 Feb 6;382(6):545-553. doi: 10.1056/NEJMoa1910607.
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 CD19-positive 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 (1×10, 1×10, or 1×10 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.).
背景
嵌合抗原受体（CAR）T 细胞疗法针对 B 细胞癌症具有显著的临床疗效。然而，CAR T 细胞会引起严重的毒性作用，并且细胞的制造过程很复杂。经过修饰表达抗 CD19 CAR 的自然杀伤（NK）细胞有可能克服这些局限性。
方法
在这项 1 期和 2 期试验中，我们给 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]）患者输注了源自脐带血的 HLA 错配抗 CD19 CAR-NK 细胞。NK 细胞通过表达编码抗 CD19 CAR、白细胞介素 15 和诱导型半胱天冬酶 9 的逆转录病毒载体进行转导，作为安全开关。细胞在体外扩增，并在淋巴细胞耗竭化疗后以三种剂量（每千克体重 1×10、1×10 或 1×10 CAR-NK 细胞）中的一种进行单次输注。
结果
CAR-NK 细胞的输注与细胞因子释放综合征、神经毒性或移植物抗宿主病的发展无关，且基线以上的炎症细胞因子（包括白细胞介素 6）水平没有升高。未达到最大耐受剂量。在接受治疗的 11 名患者中，8 名（73%）有反应；其中，7 名（4 名患有淋巴瘤，3 名患有 CLL）完全缓解，1 名缓解了 Richter 转化成分，但持续患有 CLL。在所有剂量水平下，输注后 30 天内迅速出现反应。输注的 CAR-NK 细胞至少在 12 个月内低水平扩增和持续存在。
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，且没有出现主要毒性作用。（由 MD 安德森癌症中心 CLL 和淋巴瘤登月计划以及美国国立卫生研究院资助；ClinicalTrials.gov 编号，NCT03056339）。
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