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

项目摘要/摘要--项目1 非清髓性(NMA)预适应的使用使根治性异基因干细胞移植成为可能 (AllSCT)老年患者(&gt；60岁)和那些本来不符合条件的合并疾病的患者 接近。弗雷德·哈钦森癌症研究中心和这项计划拨款开创了这一做法 在过去的20年里，方法发生了变化，并在全球范围内得到了应用。当我们继续制作 支持性护理的重要改进，最大限度地减少移植物抗宿主病(GVHD)和传染性疾病 死亡率、复发仍然是一个主要限制因素。该计划/项目解决了这一问题，并提出了新的 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 阿尔法发射体Astatine-211(211At)在条件化过程中增强疾病根除作用和2)机制 在有效治疗移植物抗白血病(GVHD)的环境中加强免疫介导的移植物抗白血病(GVL) 减刑。我们将利用新的原发急性白血病和骨髓瘤的临床前模型来研究 211At抗体结合于异基因SCT后的GVHD和GVL/GVL/GVM。随后，我们将 测试预防GVHD的方法，这些方法不太可能否定GVL，并使用这个平台来增强骨骼中的GVL 骨髓，使用临床上易处理的检查点抑制剂，删除抑制的髓系细胞和/或共刺激 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研究 移植物围术期T细胞功能与后续存活和疾病控制的关系 项目2和项目3中注解的临床队列。主要重点将是优化创新 临床前系统中用于临床翻译的免疫治疗方法。

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.