A Phase II Study of Cytokine Induced Memory-like (CIML) Natural Killer (NK) Cell Adoptive Therapy after Haploidentical Donor Hematopoietic Cell Transplantation.

摘要 华盛顿大学的骨髓移植(BMT)/白血病项目是 美国最大的，每年进行400多例移植，其中包括200多例同种异体 移植。该计划自成立以来一直隶属于BMT临床试验网络(CTN)， 最初作为凯斯西部财团的一部分，最近自2011年以来成为核心中心。在此期间 一段时间以来，我们的机构通过临床试验的积累和试验设计为CTN做出了重大贡献 输入。作为更新为核心临床中心的申请的一部分，我们建议进行II期临床试验 将一种新的细胞疗法应用于老年患者的半相合移植平台 复发的难治性急性髓细胞白血病。这一建议的基础是证明了NK细胞在体外刺激 使用细胞因子(IL12、IL15、IL18)的鸡尾酒，对后续的AML表现出增强的记忆样反应 小鼠异种移植模型的体外和体内细胞暴露。这些观察结果导致了I期剂量- 寻找临床试验以确定半相合细胞因子诱导记忆样(CIML)NK细胞作为 老年复发性急性髓细胞白血病的治疗已经结束，正在进行的第二阶段试验确定 疗效，初步结果良好。在此基础上，我们建议将这种CIML NK细胞 降低强度条件下半相合供者干细胞移植主干的探讨 以及移植后环磷酰胺对老年复发AML的治疗。我们的假设是，这是 策略将降低这一高危人群的复发率，同时保持对 降低强度的条件反射方法。完成这项研究将需要积累30名患者， 在多中心试验的情况下，预计为期两年。

Abstract The Bone Marrow Transplant (BMT)/Leukemia Program at Washington University ranks among the largest in the United States, performing over 400 transplants annually, including over 200 allogeneic transplants. The program has been affiliated with the BMT Clinical Trials Network (CTN) since its inception, initially as part of the Case Western Consortium, and more recently as a Core Center since 2011. During this time, our institution has made significant contributions to CTN through clinical trials accrual and trial design input. As part of this application for renewal as a Core Clinical Center, we propose a phase II clinical trial incorporating the use of a novel cellular therapy into a haploidentical transplant platform for elderly patients with relapsed refractory AML. The basis for this proposal is the demonstration that NK cells stimulated ex vivo with a cocktail of cytokines (IL12, IL15, IL18), exhibit an enhanced memory–like response to subsequent AML cell exposure both in vitro and in vivo in a mouse xenograft model. These observations led to a phase I dose- finding clinical trial to establish safety of haploidentical cytokine-induced memory-like (CIML) NK cells as therapy for elderly adults with relapsed AML, which has been concluded, and an ongoing phase II trial to define efficacy, with favorable preliminary results. On this basis, we propose to incorporate this CIML NK cell approach into a backbone of haploidentical donor stem cell transplantation with reduced intensity conditioning and post-transplant cyclophosphamide for elderly adults with relapsed AML. Our hypothesis is that this strategy will lower the incidence of relapse in this high risk population while preserving the tolerability of the reduced intensity conditioning approach. Completion of this study would require accrual of 30 patients, anticipated over a 2-year period in the context of a multi-center trial.