Poor immune reconstitution after haplo-identical stem cell transplantation results in high mortality from viral infections and relapse. One approach to overcome this problem is to deplete alloreactive cells selectively by deleting T cells activated by recipient stimulators, using an immunotoxin directed against the activation marker CD25. However, the degree of depletion of alloreactive cells is variable following stimulation with recipient PBMC, and this can result in GvHD. We have shown that using recipient EBV-transformed LCL as stimulators to activate donor alloreactive T cells results in more consistent depletion of in vitro alloreactivity while preserving T-cell responses to viral and potential myeloid tumor Ag. Based on these data, we have embarked on a phase I clinical dose escalation study of add-back of allo-LCL-depleted donor T cells in the haplo-identical setting, to determine if the allodepletion we achieve to allow infusion of sufficient T cells to restore useful antiviral/anti-leukemic responses without causing GvHD. Fifteen patients have so far been treated. The incidence of significant acute or chronic GvHD has been low (2/15), as has mortality from infection (1/15). Preliminary data show accelerated immune reconstitution in dose level 2 patients. Infused allodepleted donor T cells appear able to expand significantly in the face of viral reactivations, and doses as low as 3 x 10(5)/kg may be sufficient to confer useful antiviral immunity in this setting. At a median follow-up of 19.5 months, nine of 15 patients are alive and disease-free. Five patients have relapsed, all of whom have died.

中文翻译：

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在单倍体相同干细胞移植后添加异源性 T 细胞以改善免疫重建

单倍体相同干细胞移植后免疫重建不良导致病毒感染和复发的高死亡率。克服这个问题的一种方法是使用针对激活标记 CD25 的免疫毒素，通过删除受体刺激物激活的 T 细胞，选择性地消耗同种异体反应细胞。然而，在接受受体 PBMC 刺激后，同种异体反应细胞的消耗程度是可变的，这可能导致 GvHD。我们已经表明，使用受体 EBV 转化的 LCL 作为刺激物激活供体同种异体反应性 T 细胞会导致体外同种异体反应性更一致的消耗，同时保留 T 细胞对病毒和潜在髓系肿瘤 Ag 的反应。根据这些数据，我们已经开始了一项 I 期临床剂量递增研究，在单倍体相同的情况下，allo-LCL 耗尽的供体 T 细胞的添加，以确定我们实现的 allo-depletion 是否允许注入足够的 T 细胞以恢复有用的抗病毒/抗白血病反应而不引起 GvHD。迄今为止，已有 15 名患者接受了治疗。显着的急性或慢性 GvHD 的发生率很低 (2/15)，感染死亡率也很低 (1/15)。初步数据显示剂量水平 2 患者的免疫重建加速。注入的异源 T 细胞在病毒再激活时似乎能够显着扩增，低至 3 x 10(5)/kg 的剂量可能足以在这种情况下提供有用的抗病毒免疫。在中位随访 19.5 个月时，15 名患者中有 9 名存活且无病。