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用CAT修饰的T细胞治疗难治性淋巴细胞白血病

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发表于 2015-8-7 17:27:28 | 显示全部楼层 |阅读模式
Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid
Leukemia
用CAT修饰的T细胞治疗难治性淋巴细胞白血病
Abstract:
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.
摘要:
CD19嵌合抗原受体修饰的T细胞具有特异性,这已经在慢性淋巴细胞白血病(CLL)的治疗上显示出巨大的前景。嵌合抗原受体T细胞在急性淋巴细胞白血病(ALL)中是否具有的临床活性还有待考证。两个患有复发和难治前B细胞ALL的孩子在体内注入了转导的抗CD19抗体和T细胞信号传导分子,每千克体重注入1.2×10^6到 1.4×10^6CTL019细胞的剂量。在这两个患者中,CTL019 T细胞扩大到一定水平,超过1000多倍初始植入水平,并且细胞在骨髓中能检测到。此外,嵌合抗原受体的T细胞在脑脊髓液(CSF)中能被观察到,细胞在那里能保持6个月的高浓度。研究发现,细胞因子释放综合征和B细胞发育不全症都在患者中发展。其中一个孩子,细胞因子释放综合征很严重;细胞因子封锁依那西普和托珠单抗能有效地逆转综合征并没有阻止嵌合抗原受体T细胞扩张或减少抗白血病的疗效。两个病人都得到了完全缓解,其中一个病人是正在进行治疗后的第11个月得到了完全缓解。嵌合抗原受体修饰的T细胞能够在体内杀死侵略性,难治性急性白血病细胞,它使肿瘤细胞在一些ALL患者中不再表达。

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