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：
10671002
负责人：
Geoffrey Roger HILL
金额：
$ 51.06万
依托单位：
FRED HUTCHINSON CANCER 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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10671002
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 Bone marrow failure Calcineurin inhibitor Cell physiology Cells 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 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 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 permissiveness post-transplant pre-clinical preclinical study prevent programmed cell death ligand 1 programs relapse prevention 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 非清髓性（NMA）预处理的使用使得同种异体干细胞移植成为可能 (alloSCT) 的老年患者（> 60 岁）和患有合并症的患者不符合此条件弗雷德·哈钦森癌症研究中心和该计划拨款开创了这种做法。过去 20 年来，我们不断改变方法，并已在全球范围内采用，同时我们仍在继续努力。支持性护理方面的重大改进可最大限度地减少移植物抗宿主病 (GVHD) 和感染死亡率、复发仍然是一个主要限制。该计划/项目解决了这个问题并提出了新的建议。侧重于 1) 使用放射性标记的造血细胞和浆细胞靶抗体的方法 α-发射体砹211 (211At) 可增强调节过程中疾病的根除，2) 机制在 GVHD 已有效治疗的环境中增强免疫介导的移植物抗白血病 (GVL) 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其影响。 alloSCT 后 GVHD 和 GVL/ 移植物抗骨髓瘤 (GVM) 上的 211At 抗体缀合物随后我们将进行。测试不太可能消除 GVL 的 GVHD 方法，并使用该平台增强骨中的 GVL 骨髓，使用临床上易于处理的检查点抑制剂，删除抑制性骨髓细胞和/或共刺激随后，我们将利用复杂的蛋白质和转录方法来检查围移植期 T 细胞功能与后续存活和疾病控制的关系项目 2 和 3 中带注释的临床队列。主要重点是创新的优化临床前系统中的免疫治疗方法用于临床转化。