Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.
Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.
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DOI：
10.1056/nejmoa1215134
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发表时间：
2013-04-18
期刊：
影响因子：
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通讯作者：
June CH
中科院分区：
文献类型：
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作者：
Grupp SA;Kalos M;Barrett D;Aplenc R;Porter DL;Rheingold SR;Teachey DT;Chew A;Hauck B;Wright JF;Milone MC;Levine BL;June CH
具有CD 19特异性的嵌合抗原受体修饰的T细胞在慢性淋巴细胞白血病（CLL）的治疗中显示出希望。嵌合抗原受体T细胞在急性淋巴细胞白血病（ALL）中是否具有临床活性仍有待确定。2例复发性和难治性前B细胞ALL患儿接受了抗CD 19抗体和T细胞信号分子（CTL 019嵌合抗原受体T细胞）转导的T细胞输注，剂量为1.4×106至1.2×107个CTL 019细胞/kg体重。在这两名患者中，CTL 019 T细胞扩增至初始植入水平的1000倍以上，并在骨髓中鉴定出细胞。此外，在脑脊液（CSF）中观察到嵌合抗原受体T细胞，它们以高水平持续至少6个月。观察到8例3级或4级不良事件。在这两名患者中均出现了尼古丁释放综合征和B细胞发育不全。在一名儿童中，阿托伐他汀释放综合征是严重的;依那西普和托珠单抗的细胞因子阻断可有效逆转该综合征，并且不能阻止嵌合抗原受体T细胞的扩增或降低抗白血病疗效。两例患者均观察到完全缓解，1例患者在治疗后11个月仍在缓解。另一名患者在治疗后约2个月复发，原始细胞不再表达CD 19。嵌合抗原受体修饰的T细胞能够在体内杀死甚至侵袭性的、治疗难治性的急性白血病细胞。不再表达靶点的肿瘤细胞的出现表明，在一些ALL患者中，除了CD 19之外，还需要靶向其他分子。
Chimeric antigen receptor–modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre–B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×106 to 1.2×107 CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce anti-leukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor–modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.