CLINICAL TRIALS OF ALLOGENEIC STEM CELL TRANSPLANT IN LYMPHOHEMATOPOIETIC DISORDE

同种异体干细胞移植治疗淋巴造血障碍的临床试验

• 批准号: 7318393
• 负责人: Richard John O'REILLY
• 金额: $ 39.4万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318393
• 关键词: Acute; Acute leukemia; Address; Adult; Aftercare; Age; Alleles; Allogenic; Asses; B-Lymphocytes; Biology; Busulfan; CD34 gene; Cell Therapy; Cell Transplants; Chronic; Clinical Trials; Compatible; Cyclophosphamide/Fludarabine; Cytomegalovirus; Defective spinal cord development; Dose; Dysmyelopoietic Syndromes; Engraftment; Fludarabine/Melphalan; Grant; Hematologic Neoplasms; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Immunity; Immunosuppressive Agents; Immunotherapy; In Vitro; Incidence; Infection; Infusion procedures; Intravenous; Lymphoma; Malignant Neoplasms; Malignant lymphoid neoplasm; Marrow; Mitosan; Morbidity - disease rate; Myeloid Leukemia; Natural Killer Cells; Patients; Peptides; Peripheral Blood Stem Cell; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Prevention; Prophylactic treatment; Proteins; Protocols documentation; Public Health; Recurrence; Relapse; Residual Neoplasm; Residual state; Risk; Roche brand of rituximab; Siblings; Stem cell transplant; Stem cells; Syndrome; T-Lymphocyte; Techniques; Testing; Thiotepa; Toxic effect; Transplant Recipients; Transplantation; Treatment Protocols; Umbilical Cord Blood; Viremia; Virus Diseases; WT1 Protein; Whole-Body Irradiation; chemotherapy; conditioning; cytokine; design; fludarabine; graft vs host disease; graft vs leukemia effect; improved; keratinocyte growth factor; leukemia; mortality; novel; novel therapeutics; older patient; prevent; programs; reconstitution; rituximab; success

Project 6 proposes clinical trials testing new therapeutic strategies designed to reduce the morbidity, non- leukemic mortality and incidence of relapse associated with allogenic hematopoietic cell transplants (HSCT) applied to the treatment of acute leukemias and myelpdysplastic syndromes (MDS), particularly in older patients and in patients lacking an HLA-matched sibling donor. The project includes 8 clinical trials organized under 3 specific aims. Specific aim 1 includes 2 phase II clinical trials testing the potential of keratinocyte growth factor (KGF) to reduce transplant-related mortality and enhance DPS by reducing early toxicity and stimulating thymopoiesis and T cell reconstitution in adults (median age >50)with hematologic malignancies receiving HLA- matched or 1-2 allele disparate CD34+ E- T cell depleted PBSC grafts from related or unrelated donors after treatment with myeloablative conditioning regimens developed in this grant period. Specific Aim 2, proposes two trials of double unit cord blood transplants,the first (Aim 2A) a trial of double UCBT myeloablative conditioning to patients with acute leukemias, MDS and advanced NHL who lack an 8-10 allele related or unrelated donor; the second (Aim 2B) a trail of double UCBT administered after a novel nonmyeloablative regimen including Rituximab in patients with lymphomas responsive to a GVL effect. These trials each include correlative analyses designed to identify cord blood graft and host features that determine the selective engraftment of 1 UCBT in a given allogenic host. As developed in this center, TCD marrow or PBSC transplants have achieved consistent engraftment with a low incidence of GVHD without use of post-transplant drug prophylaxis. Effective prevention of GVHD thus allows us to critically examine adoptive cell therapies and immunostimulatory cytokine in the absence of concurrently administered immuno-suppressive drugs or biologicals. Specific Aim 3 addresses this objective in 3 trials. Aim 3A is a phase I trial of T cells sensitized by a new technique employing overlapping 15-mer peptides spanning CMV-pp65 for treatment of patients with persistent CMV viremia or infection. In Aim 3B, we propose a phase I trial of T cells sensitized with overlapping 15-mer peptides spanning the sequence of the WT1 protein for treatment of patients with minimal residual disease or recurrence of WT-1 + acute leukemias, MDS and blastic CML post transplant. Aim 3C proposes a pilot phase II trial of adoptive therapy with in vitro isolated, HLA haploidentical NK cells following stem cell-sparing chemotherapy for patients relapsing in the first year post transplant with AMI, ALL and blastic CML. Relevance to Public Health: These trials test novel transplant strategies which show promise of improving prospects for sustained DPS in adults with acute leukemia, MDS and lymphoma, particularly older patients and patients lacking a matched sibling donor. They will also test adoptive therapies which may be broadly applied to patients with severe viral infection or leukemia relapse.

项目 6 提议进行临床试验，测试旨在降低发病率、非 与同种异体造血细胞移植（HSCT）相关的白血病死亡率和复发率 适用于治疗急性白血病和骨髓增生异常综合征（MDS），特别是老年患者 以及缺乏 HLA 匹配的兄弟姐妹捐赠者的患者。该项目包括 3 项组织下的 8 项临床试验 具体目标。具体目标 1 包括 2 项 II 期临床试验，测试角质形成细胞生长因子的潜力 (KGF) 通过减少早期毒性和刺激来降低移植相关死亡率并增强 DPS 接受 HLA- 治疗的血液恶性肿瘤成人（中位年龄 >50 岁）的胸腺生成和 T 细胞重建 匹配或 1-2 个等位基因不同的 CD34+ E-T 细胞耗尽的 PBSC 移植物来自相关或无关的供体 在此资助期间开发的清髓预处理方案进行治疗。具体目标2，提出两个 双单位脐带血移植试验，第一个（目标 2A）双 UCBT 清髓调理试验 缺乏 8-10 等位基因相关或无关供体的急性白血病、MDS 和晚期 NHL 患者；这 第二个（目标 2B）在包括利妥昔单抗在内的新型非清髓性治疗方案后进行双 UCBT 试验 对 GVL 效应有反应的淋巴瘤患者。这些试验均包括设计的相关分析 识别脐带血移植物和宿主特征，从而决定 1 UCBT 在给定环境中的选择性植入 同种异体宿主。 正如该中心所开发的，TCD 骨髓或 PBSC 移植已实现一致的植入，且成本较低 不使用移植后药物预防的 GVHD 发生率。有效预防 GVHD 使我们能够 在没有同时进行的情况下严格检查过继细胞疗法和免疫刺激细胞因子 给予免疫抑制药物或生物制品。具体目标 3 通过 3 次试验来实现这一目标。目的 图 3A 是一项 T 细胞的 I 期试验，该试验采用了一种新技术，该技术采用了重叠的 15 聚体肽，跨越 CMV-pp65 用于治疗持续性 CMV 病毒血症或感染患者。在目标 3B 中，我们提出第一阶段 用跨越 WT1 蛋白序列的重叠 15 聚体肽致敏的 T 细胞试验 治疗有微小残留病或复发的 WT-1 + 急性白血病、MDS 和急变性患者 移植后慢性粒细胞白血病。 Aim 3C 提议进行体外分离的 HLA 过继治疗的 II 期试验 保留干细胞化疗后第一年复发的患者的半相合 NK 细胞 患有 AMI、ALL 和急变性 CML 的移植。与公共卫生的相关性：这些试验测试新型移植 这些策略有望改善急性白血病、MDS 和成人患者持续 DPS 的前景 淋巴瘤，特别是老年患者和缺乏匹配的兄弟姐妹捐赠者的患者。他们还将测试收养 可能广泛应用于严重病毒感染或白血病复发患者的疗法。