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 (1×105, 1×106, or 1×107 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.).

中文翻译：

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CAR转导的自然杀伤细胞在CD19阳性淋巴瘤中的用途。

背景技术抗CD19嵌合抗原受体（CAR）T细胞疗法在B细胞癌中显示出显着的临床功效。然而，CAR T细胞可诱导明显的毒性作用，并且细胞的制造是复杂的。经过修饰以表达抗CD19 CAR的自然杀伤（NK）细胞具有克服这些局限性的潜力。方法在1期和2期试验中，我们对11例复发或难治性CD19阳性癌症（非霍奇金淋巴瘤或慢性淋巴细胞性白血病[CLL]）的患者给予了脐带血HLA不匹配的抗CD19 CAR-NK细胞。用表达编码抗CD19 CAR，白介素15和诱导型胱天蛋白酶9作为安全开关的基因的逆转录病毒载体转导NK细胞。将细胞离体扩增，并以三种剂量（1×105，淋巴结清扫化疗后，每千克体重1×106或1×107 CAR-NK细胞。结果CAR-NK细胞的给药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，并且包括白细胞介素6在内的炎性细胞因子的水平也没有增加。未达到最大耐受剂量。在接受治疗的11位患者中，有8位（73％）有反应；在这些患者中，7例（4例淋巴瘤和3例CLL）完全缓解，1例Richter转化成分缓解，但CLL持续存在。反应迅速，并且在所有剂量水平的输注后30天内可见。注入的CAR-NK细胞扩增并以低水平持续至少12个月。结论在11例CD19阳性复发或难治性癌症患者中，大多数对CAR-NK细胞的治疗有反应，而没有产生重大毒性作用。（由MD安德森癌症中心CLL和淋巴瘤Moonshot和美国国立卫生研究院资助； ClinicalTrials.gov编号，NCT03056339。）。