Serrano Lisa Marie, Pfeiffer Timothy, Olivares Simon, Numbenjapon Tontanai, Bennitt Jennifer, Kim Daniel, Smith David, McNamara George, Al-Kadhimi Zaid, Rosenthal Joseph, Forman Stephen J, Jensen Michael C, Cooper Laurence J N
University of Texas M. D. Anderson Cancer Center, Pediatrics Research Unit 853, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Blood. 2006 Apr 1;107(7):2643-52. doi: 10.1182/blood-2005-09-3904. Epub 2005 Dec 13.
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 hematopoietic 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.
疾病复发是B系急性淋巴细胞白血病（B-ALL）患者接受非亲缘脐血移植（UCBT）后实现治疗成功的障碍。虽然过继转移供体来源的肿瘤特异性T细胞在概念上是异基因造血干细胞移植后消除残留疾病的一种有吸引力的方法，但UCBT后的过继免疫疗法受到从功能上未成熟的脐血（UCB）来源的T细胞产生抗原特异性T细胞的困难的限制。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B系抗原CD19的特异性，并在UCB来源的T细胞中表达该转基因。已经开发出一种符合当前T细胞试验良好生产规范的体外方法，用于对UCB来源的T细胞进行基因改造并在数量上进行扩增，使其成为CD19特异性效应细胞。这些细胞能够在体外产生受CD19限制的细胞因子并进行细胞溶解，还能介导CD19+肿瘤的消退，并在体内被选择性清除。此外，对基因改造的T细胞克隆进行的延时显微镜观察显示，它们具有特异性且重复性地裂解CD19+肿瘤细胞的能力。这些数据为在UCBT后输注UCB来源的CD19特异性T细胞以降低CD19+B-ALL复发率提供了理论依据。
