Immunobiology for Marrow Allografts for Leukemia

白血病同种异体骨髓移植的免疫生物学

• 批准号: 9277360
• 负责人: Richard John O'REILLY
• 金额: $ 292.82万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277360
• 关键词: Acute leukemia; Address; Adjuvant Therapy; Adoptive Immunotherapy; Adoptive Transfer; Affect; Algorithms; Alleles; Allogenic; Allografting; Antibodies; Antigen-Presenting Cells; Basic Science; Biological; Biostatistics Core; Cell physiology; Cells; Clinical; Clinical Research; Clinical Trials; Complex; Conduct Clinical Trials; Cytomegalovirus; Cytomegalovirus Infections; Dendritic Cells; Development; Disease; Donor person; Drug or chemical Tissue Distribution; Dysmyelopoietic Syndromes; Elderly; Enteral; Epithelial; Epithelial Cells; Epitopes; Evaluation; Focal Infection; Fostering; Goals; Hematopoietic; Hematopoietic Neoplasms; Histocompatibility; Homologous Transplantation; Host resistance; Human Herpesvirus 4; Immune; Immunity; Immunobiology; Immunotherapy; Impairment; Incidence; Infection; Inflammation; Injury; Intestines; Janus kinase 2; Lead; Leuprolide; Ligands; Lymphoid Cell; Marrow; Microbe; Monoclonal Antibodies; Morbidity - disease rate; Natural Immunity; Natural Killer Cells; Outcome; Patients; Peptides; Preparation; Prevention; Recovery; Recurrence; Refractory Disease; Regimen; Regulation; Relapse; Research; Research Project Grants; Resistance; Resistance to infection; Risk; Role; Sampling; Signaling Molecule; Stimulus; Systemic infection; T cell therapy; T-Cell Receptor; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Tissues; Toxic effect; Transplant Recipients; Transplantation; Treatment Effectiveness; Tumor Antigens; Umbilical Cord Blood; Vaccines; Virus; WT1 gene; acute toxicity; anergy; antimicrobial; base; c new; cancer type; cellular engineering; cellular transduction; chimeric antigen receptor; conditioning; high risk; immunogenic; improved; in vivo; inhibitor/antagonist; interleukin-22; leukemia; monocyte; mortality; multidisciplinary; novel strategies; novel therapeutics; novel vaccines; older patient; pathogen; prevent; programs; receptor; reconstitution; repaired; response; success; therapeutic evaluation; therapy design; tumor

DESCRIPTION (provided by applicant): We propose an integrated, multidisciplinary program of basic and clinical research addressing challenges to the success of allogeneic HSCT used to treat of AML, ALL and MDS in older adults and patients lacking a histocompatible donor. The program's central theme of this program is: The exploration of novel approaches whereby injuries to normal host tissues induced by conditioning, infection and GVHD can be reduced or prevented, and resistance to pathogens and recurrent leukemia selectively enhanced. The program includes 6 research projects and 3 cores. Project 1 examines NK cell development, the role of KIR engagement of HLA ligand expressed by host and donor in modulating NK function, and, particularly, the contributions of activating KIRs, 2DS1 and 3Ds1 to resistance against leukemic relapse and CMV infections. Project 2 examines receptor ligand interactions governing monocyte response to stimuli from the microflora including their activation, mobilization and tissue distribution, and their capacity to both stimulate and participate in GVHD. Project 3 examines how T-cells when stimulated with allogeneic monocyte-derived dendritic cells in the presence of JAK-2 inhibitors induced into a durable state of anergy and the effects of JAK-2 inhibitors on responses are tumor antigens presented by other functionally distinct types of dendritic cells. Project 4 evaluates the regulation of IL-22, its role in the stimulation of enteri and thymic epithelial repair and its potential to reduce toxicities, modulate GVHD and enhance resistance to infection. Project 5 tests new monoclonal antibodies specific for WT1 peptide/HLA complexes, long-lived EBV T-cells transduced to express TCRs or chimeric antigen receptors specific for WT1/HLA complexes and new heteroclitic vaccines for adoptive immunotherapy of WT-1+ leukemias, Project 6 proposes 6 clinical trials testing new conditioning and both T-cell depleted and cord blood HSCT to reduce toxicities, potentiate hematopoietic and thymopoietic recovery and reduce TRM and new adoptive T-cell therapies for CMV infections or recurrent leukemia . The 3 cores include: Core A which provides all patient samples and evaluate grafts pre and post HSCT, Core B Biostatistics and Core C administrative support and oversight.

描述（由申请人提供）：我们提出了一个综合的，多学科的基础和临床研究计划，解决了用于治疗老年人和缺乏组织相容性供体的AML，ALL和MDS患者的同种异体HSCT成功的挑战。该计划的中心主题是：探索新的方法，从而减少或预防由条件反射，感染和GVHD引起的正常宿主组织损伤，并选择性地增强对病原体和复发性白血病的抵抗力。该计划包括6个研究项目和3个核心。项目1研究NK细胞的发育，宿主和供体表达的HLA配体的KIR参与调节NK功能的作用，特别是激活KIR，2DS 1和3DS 1对白血病复发和CMV感染的抗性的贡献。项目2研究了受体配体相互作用，控制单核细胞对微生物刺激的反应，包括它们的激活，动员和组织分布，以及它们刺激和参与GVHD的能力。项目3研究了在JAK-2抑制剂的存在下，T细胞在用同种异体单核细胞衍生的树突状细胞刺激时如何诱导成持久的无反应性状态，以及JAK-2抑制剂对反应的影响是由其他功能不同类型的树突状细胞呈递的肿瘤抗原。项目4评估了IL-22的调节、其在刺激肠和胸腺上皮修复中的作用及其降低毒性、调节GVHD和增强对感染的抵抗力的潜力。项目5测试了对WT 1肽/HLA复合物特异性的新单克隆抗体，转导以表达TCR或对WT 1/HLA复合物特异性的嵌合抗原受体的长寿命EBV T细胞，以及用于WT-1+白血病的过继免疫治疗的新异源疫苗，项目6提出了6项临床试验，测试新的预处理以及T细胞耗竭和脐带血HSCT以降低毒性，增强造血和胸腺恢复，减少TRM和新的过继性T细胞疗法用于CMV感染或复发性白血病。这三个核心包括：核心A，提供所有患者样本并评价HSCT前后的移植物;核心B，生物统计学;核心C，行政支持和监督。