Allogeneic stem cell transplant with grafts depleted of naive T cells for leukemi

使用去除初始 T 细胞的移植物进行同种异体干细胞移植治疗白血病

• 批准号: 8495284
• 负责人: Marie Bleakley
• 金额: $ 17.01万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-08 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495284
• 关键词: Acute Graft Versus Host Disease; Acute leukemia; Adoptive Immunotherapy; Adoptive Transfer; Alleles; Allogenic; Animals; Antigens; Binding; Blood typing procedure; Bone Marrow; CD8B1 gene; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Conduct Clinical Trials; Cytolysis; Cytotoxic T-Lymphocytes; Development; Disease-Free Survival; Donor Lymphocyte Infusion; Dysmyelopoietic Syndromes; Engraftment; Enrollment; Environment; Evaluation; Excision; Flow Cytometry; Foundations; Fred Hutchinson Cancer Research Center; Funding; Future; Generations; Genes; Genetic; Goals; Health; Hematopoietic; Hematopoietic Stem Cell Transplantation; Histocompatibility; Human; Immune; Immunity; Immunobiology; Immunologic Monitoring; Immunology; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Kinetics; Laboratories; Libraries; Life; Mediating; Mentors; Minor; Modality; Modeling; Mus; NOD/SCID mouse; Opportunistic Infections; Patients; Peptides; Peripheral Blood Stem Cell; Pharmacotherapy; Phase; Prevention; Principal Investigator; Protocols documentation; Recovery; Relapse; Research; Research Activity; Research Personnel; Severities; Siblings; Staining method; Stains; Stem cell transplant; Stem cells; T memory cell; T-Cell Depletion; T-Lymphocyte; Testing; Tissues; Toxic effect; Training; Training Activity; Translating; Translational Research; Transplant Recipients; Transplantation; Vaccines; Viral; bacterial H antigen; career; cohort; design; experience; genetic linkage analysis; genome wide association study; graft vs host disease; human stem cells; human study; improved; insight; leukemia; non-genetic; novel; novel strategies; pathogen; peripheral blood; phase 2 study; prevent; progenitor; reconstitution; research study; selective expression; skills

DESCRIPTION (provided by applicant): The candidate's career goal is to become a principal investigator of a translational immunology laboratory that will develop new approaches to improve the disease-free survival of patients with leukemia that receive allogeneic hematopoietic stem cell transplantation (HCT). Specifically, the candidate aspires to develop immunotherapies to augment the graft versus leukemia (GVL) effect and thereby reduce the rates of relapse following HCT, and strategies to reduce the life-threatening immunological complications of HCT including graft versus host disease (GVHD). In the immediate term, the candidate aims to gain experience in translating her research to the clinic as the Principal Investigator of the clinical trial entitled "A Multi-center Phase II Study of Selective Depletion of CD45RA+ T Cells from Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD (FHCRC Protocol 2222)", to develop further skills in antigen identification, and to become independent in designing, conducting, interpreting and funding her research. The research activities planned include the conduct and evaluation of the clinical trial of naive T cell depletion and associated immune reconstitution studies, and antigen discovery studies to generate a library of human minor histocompatibility (H) antigens. The candidate will obtain training in clinical trials, advanced flow cytometry, statistical analysis of immune monitoring, genetic linkage analysis and genome-wide association studies. The research and training activities will be primarily conducted at the Fred Hutchinson Cancer Research Center which is a superb environment for translational and clinical research, particularly in the field of HCT. The candidate will be mentored by Dr. Stanley Riddell, an experienced and successful mentor who has a distinguished career in the fields of translational immunology, immunotherapy and HCT. The applicant participated in all phases of development of the clinical trial, which is a novel, first-in-human study that will provide insights into the immunobiology of GVHD and the recovery of protective T cell immunity in recipients of stem cell grafts that contain a limited number of memory T cells. This approach may result in a new modality for allogeneic HCT with less GVHD and better immune reconstitution. The studies proposed in Aim 3 will employ new strategies for minor H antigen discovery and assist in laying the foundation for future immunotherapeutic approaches to the problem of relapse of leukemia after HCT. The specific aims are: 1. To determine whether transplantation of stem cell grafts depleted of TN is safe and reduces GVHD in HLA identical related donor stem cell transplant recipients. 2. To evaluate reconstitution of pathogen-specific TM and TN cells in recipients of HLA matched related stem cell grafts depleted of TN. 3. To develop a library of novel minor H antigens that are expressed selectively on hematopoietic cells including acute leukemia and presented in association with prevalent HLA alleles.

描述（由申请人提供）：候选人的职业目标是成为转化免疫学实验室的主要研究者，该研究人员将开发新的方法来改善接受同种异性造血干细胞移植（HCT）的白血病患者的无疾病生存。具体而言，候选人渴望开发免疫疗法以增加移植物与白血病（GVL）效应，从而降低HCT后HCT后的复发率，以及减少HCT（包括GRAFT与宿主疾病（GVHD））的HCT免疫并发症的策略。 In the immediate term, the candidate aims to gain experience in translating her research to the clinic as the Principal Investigator of the clinical trial entitled "A Multi-center Phase II Study of Selective Depletion of CD45RA+ T Cells from Allogeneic Peripheral Blood Stem Cell Grafts for the Prevention of GVHD (FHCRC Protocol 2222)", to develop further skills in antigen identification, and to become independent in designing,进行，解释和资助她的研究。计划的研究活动包括对幼稚T细胞耗竭和相关免疫结构研究的临床试验的行为和评估，以及抗原发现研究，以生成人类次要组织相容性（H）抗原的库。候选人将获得临床试验，晚期流式细胞仪，免疫监测的统计分析，遗传连锁分析和全基因组关联研究的培训。研究和培训活动将主要在弗雷德·哈钦森癌症研究中心进行，这是转化和临床研究的绝佳环境，尤其是在HCT领域。候选人将由经验丰富且成功的导师斯坦利·里德尔（Stanley Riddell）博士指导，他在转化免疫学，免疫疗法和HCT领域具有杰出的职业。申请人参与了临床试验发展的所有阶段，这是一项新颖的人类研究，它将提供对GVHD免疫生物学的见解，并在含有有限的存储器T细胞的干细胞移植物中恢复了GVHD的免疫学和保护性T细胞免疫。这种方法可能会导致GVHD较少和更好的免疫重建的同种异体HCT的新方式。 AIM 3中提出的研究将采用新的策略来进行较小的H抗原发现，并为未来的免疫治疗方法奠定基础，以解决HCT后白血病复发的问题。具体目的是：1。确定TN耗尽的干细胞移植物的移植是否安全，并减少HLA相同相关的供体干细胞移植受者的GVHD。 2。评估在HLA匹配的相关干细胞移植物中，病原体特异性TM和TN细胞的重构。 3。开发一个新型的小型H抗原库，这些库在包括急性白血病在内的造血细胞上有选择地表达，并与普遍的HLA等位基因相关。