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

单倍相合供体造血细胞移植后细胞因子诱导记忆样 (CIML) 自然杀伤 (NK) 细胞过继治疗的 II 期研究。

• 批准号: 10657635
• 负责人: Iskra Pusic
• 金额: $ 16.19万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-27 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10657635
• 关键词: Acute Myelocytic Leukemia; Adoptive Cell Transfers; Adult; Age; Allogenic; Bone Marrow Transplantation; Cell Therapy; Cellular immunotherapy; Clinical; Clinical Trials; Clinical Trials Network; Correlative Study; Cyclophosphamide; Disease; Dose; Elderly; Environment; Evaluable Disease; Exhibits; Goals; Haptens; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Homologous Transplantation; IL18 gene; Immune; Immunology; In Vitro; Incidence; Institution; Interleukin-12; Interleukin-15; Longevity; Mediating; Memory; Multicenter Trials; Mus; Natural Killer Cell Immunotherapy; Natural Killer Cells; Outcome; Patients; Phase; Phase II Clinical Trials; Population; Prognosis; Proliferating; Property; Prophylactic treatment; Refractory; Relapse; Reporting; Risk Reduction; Safety; Stem cell transplant; Time; Toxic effect; Transplantation; United States; Universities; Vertebral column; Virus Diseases; Washington; Xenograft Model; acute myeloid leukemia cell; clinical center; conditioning; cytokine; donor stem cell; effective therapy; experimental study; first-in-human; graft vs host disease; graft vs leukemia effect; hematopoietic cell transplantation; high risk; high risk population; human study; in vivo; leukemia; mortality; mouse model; novel; older patient; phase 2 study; phase II trial; post-transplant; preservation; programs; relapse risk; response; trial design

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.

摘要 华盛顿大学的骨髓移植（BMT）/白血病项目是世界上 在美国最大的，每年进行400多例移植，包括200多例同种异体移植。 移植该计划自成立以来一直隶属于BMT临床试验网络（CTN）， 最初作为凯斯西方财团的一部分，最近自2011年以来作为核心中心。在此 同时，我们的机构通过临床试验的累积和试验设计为CTN做出了重大贡献 输入.作为核心临床中心更新申请的一部分，我们提议进行II期临床试验 将新型细胞疗法的使用纳入老年患者的单倍相合移植平台 复发性难治性AML该建议的基础是证明NK细胞刺激离体 与细胞因子（IL 12、IL 15、IL 18）的混合物一起，对随后的AML表现出增强的记忆样应答。 在小鼠异种移植模型中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，以确定单倍相合的精氨酸诱导的记忆样（CIML）NK细胞作为 一项正在进行的II期试验， 效果良好，初步效果良好。在此基础上，我们建议将这种CIML NK细胞 降低强度预处理的单倍体相合供体干细胞移植骨干的研究 和移植后环磷酰胺用于复发性AML的老年人。我们的假设是 该策略将降低这一高危人群的复发率，同时保留患者的耐受性。 降低强度条件反射方法。完成本研究需要招募30例患者， 在多中心试验的背景下，预计在2年内。