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

项目总结/摘要-项目1 非清髓性（NMA）预处理的使用允许治愈性异基因干细胞移植 老年患者（> 60岁）和患有合并症的患者（alloSCT），否则将不符合此条件 approach.弗雷德哈钦森癌症研究中心和这项计划拨款开创了这种做法 在过去的20年里，它改变了方法，并在全球范围内得到了采用。虽然我们继续使 支持性治疗的重要改进，最大限度地减少了移植物抗宿主病（GVHD）和感染性疾病， 死亡率，复发仍然是一个主要的限制。该计划/项目解决了这一问题，并提出了新的 这些方法集中于1）使用用放射性标记的造血和浆细胞靶抗体， α-发射体<$-211（211 At）在条件反射期间增强疾病根除的机制，以及2） 增强免疫介导的移植物抗白血病（GVL）的设置，其中GVHD已被有效地 减轻。我们将利用新的原发性急性白血病和骨髓瘤的临床前模型来研究 211 At-抗体偶联物对alloSCT后GVHD和GVL/移植物抗骨髓瘤（GVM）的影响。随后，我们将 测试不太可能消除GVL的GVHD预防方法，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/或共刺激细胞， 激动剂随后，我们将利用复杂的蛋白质和转录为基础的方法来检查， 移植前后T细胞功能与随后的存活率和疾病控制的关系， 项目2和3中的注释临床队列。一个主要的重点将是优化创新 临床前系统中的免疫治疗方法用于临床转化。

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.