Project 1: Promoting Graft-versus-Tumor Effects in the Bone Marrow

项目 1：促进骨髓中的移植物抗肿瘤效应

基本信息

批准号：
10266073
负责人：
Geoffrey Roger HILL
金额：
$ 38.06万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-12 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10266073
关键词：
Acute Graft Versus Host Disease Acute leukemia Address Adrenal Cortex Hormones Agonist Alloantigen Allogenic Antigen Presentation Antigen-Presenting Cells Aplastic Anemia Astatine Bioinformatics Bone Marrow Calcineurin inhibitor Cell physiology Chronic Clinic Clinical Clinical Oncology Clinical Trials Combination immunotherapy Computer Analysis Cyclophosphamide Data Development Discipline Disease Disease Progression Elderly Epigenetic Process Flow Cytometry Fred Hutchinson Cancer Research Center Gastrointestinal tract structure Genetic Transcription Genomics Graft-Versus-Tumor Induction Grant Hematologic Neoplasms Hematopoietic Hematopoietic Neoplasms Human Immune Immune checkpoint inhibitor Immunity Immunologic Deficiency Syndromes Immunology Immunosuppression Immunotherapy Inflammation Inflammatory Intervention Life Ligands Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Marrow Mediating Morbidity - disease rate Multiple Myeloma Mus Myeloid-derived suppressor cells Natural Killer Cells Non-Malignant Opportunistic Infections Outcome PTPRC gene Pancytopenia Pathogenicity Pathway interactions Patients Phenotype Plasma Cells Pre-Clinical Model Prevention Procedures Proteins Radiation Radioimmunoconjugate Radioimmunotherapy Radioisotopes Recurrent disease Relapse Resistance Severe Combined Immunodeficiency Signal Transduction Stem cell transplant Supportive care System T cell differentiation T cell response T-Lymphocyte Testing Therapeutic Tissues Toxic effect Translations Transplantation Tumor Promotion Whole-Body Irradiation Work antibody conjugate base checkpoint inhibition chemoradiation clinical development clinical translation cohort comorbidity conditioning curative treatments cytokine disorder control exhaustion graft vs host disease graft vs leukemia effect immune reconstitution improved innovation leukemia mortality novel novel strategies older patient pathogen post-transplant pre-clinical preclinical study prevent programmed cell death ligand 1 programs response synergism therapeutically effective tumor

项目摘要

PROJECT SUMMARY / ABSTRACT – Project 1 The use of non-myeloablative (NMA) conditioning has allowed curative allogeneic stem cell transplantation (alloSCT) of older patients (>60yrs) and those with co-morbidities that would otherwise be ineligible for this approach. The Fred Hutchinson Cancer Research Center and this program grant have pioneered this practice changing approach over the last 20 years and it has been taken up globally. While we have continued to make important improvements in supportive care that minimize graft-versus host disease (GVHD) and infectious mortality, relapse remains a major limitation. This program/project addresses this issue and proposes new approaches that focus on 1) the use of hematopoietic and plasma cell target antibodies radiolabeled with the alpha-emitter astatine-211 (211At) to enhance disease eradication during conditioning and 2) mechanisms to enhance immune-mediated Graft-versus-Leukemia (GVL) in settings where GVHD has been effectively mitigated. We will utilize novel preclinical models of primary acute leukemia and myeloma to study the effects of 211At-antibody conjugates on GVHD and GVL/ Graft-versus-Myeloma (GVM) after alloSCT. Subsequently we will test approaches to prevent GVHD that are unlikely to negate GVL, and use this platform to enhance GVL in bone marrow, using clinically tractable checkpoint inhibitors, deletion of suppressive myeloid cells and/or costimulatory agonists. Subsequently we will utilize sophisticated protein and transcriptional based approaches to examine the relationship of T cell function in the peri-transplant period to subsequent survival and disease control in well- annotated clinical cohorts within Projects 2 and 3. A major focus will be the optimization of innovative immunotherapy approaches in preclinical systems for clinical translation.

项目摘要 /摘要 - 项目1 使用非毛囊（NMA）调节已允许治愈同种异体干细胞移植（同类）老年患者（> 60岁）和患有合并症的患者，否则将不合资格方法。弗雷德·哈钦森癌症研究中心和该计划赠款率先开创了这种做法在过去的20年中，不断变化的方法已在全球范围内采用。虽然我们继续做支持护理的重要改善，以最大程度地减少移植物宿主疾病（GVHD）和感染力死亡率，继电器仍然是一个主要限制。这个程序/项目解决了这个问题，并提出了新的建议侧重于1）使用造血和浆细胞靶抗体放射性标记的方法 α-释放器astatine-211（211AT），以增强调节过程中的消除疾病和2）机制在GVHD有效地，增强免疫介导的移植物与白血病（GVL）缓解。我们将利用原发性急性白血病和骨髓瘤的新型临床前模型来研究 AlloSCT后，GVHD和GVL/ GRAFT-versus-Myeloma（GVM）上的211AT抗体结合。随后我们会预防不太可能否定GVL的GVHD的测试方法，并使用此平台来增强骨骼的GVL 骨髓，使用临床上可牵引的检查点抑制剂，抑制性髓样细胞的缺失和/或costumulation 激动剂。随后，我们将利用复杂的蛋白质和基于转录的方法来检查 T细胞功能在移植期的关系与随后的生存和疾病控制的关系项目2和3中的带注释的临床人群。主要重点是优化创新用于临床翻译的临床前系统中的免疫疗法方法。