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提出了临床试验测试新的治疗策略，旨在减少发病率，非 白血病死亡率和复发率与异基因造血细胞移植（HSCT）相关 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匹配同胞供者的患者。该项目包括8项临床试验， 明确的目标。具体目标1包括2个II期临床试验测试角质细胞生长因子的潜力 (KGF)降低移植相关死亡率，并通过减少早期毒性和刺激 接受HLA-1治疗的恶性血液病成人（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CD 34 + E-T细胞耗尽的PBSC移植物，来自相关或无关供体， 清髓性预处理方案的治疗，在此期间开发的赠款。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清髓性预处理试验， 缺乏8-10等位基因相关或不相关供体的急性白血病、MDS和晚期NHL患者; 第二个（目标2B）是在包括利妥昔单抗在内的新型非清髓性方案后给予双倍UCBT的试验 在对GVL效应有反应的淋巴瘤患者中。这些试验均包括相关分析， 确定脐带血移植物和宿主的特征，这些特征决定了在给定的移植物中选择性植入1个UCBT。 同种异体宿主 如本中心所开发的，TCD骨髓或PBSC移植已实现了持续的植入， 未使用移植后药物预防的GVHD发生率。因此，有效预防GVHD使我们能够 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剂。具体目标3在3项试验中解决了这一目标。目的 3A是通过采用重叠的15-mer肽跨越的新技术致敏T细胞的I期试验。 CMV-pp 65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WT 1蛋白序列的重叠15聚体肽致敏T细胞的试验， 治疗WT-1 +急性白血病、MDS和母细胞白血病的微小残留病或复发患者 移植后CML。目的3C提出了一个初步的II期试验，采用体外分离的HLA进行过继治疗， 保留干细胞化疗后第一年复发患者的单倍体相合NK细胞 急性淋巴细胞白血病（ALL）和急变型慢性粒细胞白血病（CML）。与公共卫生的相关性：这些试验测试了新的移植 这些策略显示出改善急性白血病、MDS和 淋巴瘤，特别是老年患者和缺乏匹配的同胞供体的患者。他们还将测试收养 可广泛应用于严重病毒感染或白血病复发患者的治疗。