Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posarcansplantation adoptive immunotherapy
Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posarcansplantation adoptive immunotherapy
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DOI：
10.1182/blood-2005-09-3904
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发表时间：
2006-04-01
期刊：
影响因子：
20.3
通讯作者：
Cooper, LJN
中科院分区：
文献类型：
--
作者：
Serrano, LM;Pfeiffer, T;Cooper, LJN
非亲缘脐带血移植（UCBT）治疗B系急性淋巴细胞白血病（B-ALL）后，疾病复发是获得治疗成功的障碍。虽然供体来源的肿瘤特异性T细胞的过继转移在概念上是消除同种异体造血干细胞移植后残留疾病的有吸引力的方法，但UCBT后的过继免疫治疗受到难以从功能性幼稚脐带血（UCB）来源的T细胞产生抗原特异性T细胞的限制。因此，为了产生识别B-ALL的T细胞，我们开发了一种嵌合免疫受体，以重定向T细胞对CD 19（一种B系抗原）的特异性，并在UCB衍生的T细胞中表达这种转基因。已经开发了一种离体方法，该方法符合当前T细胞试验的良好生产规范，用于对UCB衍生的T细胞进行遗传修饰并在数字上扩增为CD 19特异性效应细胞。这些能够在体外产生和溶解CD 19限制性细胞因子，以及介导CD 19（+）肿瘤的消退和在体内被选择性消除。此外，转基因T细胞克隆的延时显微镜显示了特异性和重复性裂解CD 19（+）肿瘤细胞的能力。这些数据为UCBT后输注脐血来源的CD 19特异性T细胞以降低CD 19（+）B-ALL复发率提供了理论依据。
Disease relapse is a barrier to achieving therapeutic success after unrelated umbilical cord-blood transplantation (UCBT) for B-lineage acute lymphoblastic leukemia (B-ALL). While adoptive transfer of donor-derived tumor-specific T cells is a conceptually attractive approach to eliminating residual disease after allogeneic hematopoletic stem cell transplantation, adoptive immunotherapy after UCBT is constrained by the difficulty of generating antigen-specific T cells from functionally naive umbilical cord-blood (UCB)-derived T cells. Therefore, to generate T cells that recognize B-ALL, we have developed a chimeric immunoreceptor to redirect the specificity of T cells for CD19, a B-lineage antigen, and expressed this transgene in UCB-derived T cells. An ex vivo process, which is compliant with current good manufacturing practice for T-cell trials, has been developed to genetically modify and numerically expand UCB-derived T cells into CD19-specific effector cells. These are capable of CD19-restricted cytokine production and cytolysis in vitro, as well as mediating regression of CD19(+) tumor and being selectively eliminated in vivo. Moreover, time-lapse microscopy of the genetically modified T-cell clones revealed an ability to lyse CD19(+) tumor cells specifically and repetitively. These data provide the rationale for infusing UCB-derived CD19-specific T cells after UCBT to reduce the incidence of CD19(+) B-ALL relapse.