Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies

优化造血干细胞移植治疗血液恶性肿瘤

• 批准号: 10001462
• 负责人: John F. Dipersio
• 金额: $ 91.49万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-07 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001462
• 关键词: Acute Myelocytic Leukemia; Acute T Cell Leukemia; Affinity; Allogenic; Area; Back; Basic Science; Bispecific Antibodies; Bone Marrow; CD7 gene; CRISPR/Cas technology; CXCL12 gene; CXCR4 gene; Chemosensitization; Clinical Research; Clinical Trials; Complication; Disease; Effector Cell; Engraftment; Failure; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homing; IFNGR1 gene; IL3RA gene; IL8RB gene; Immune; Immunotherapeutic agent; Immunotherapy; Infusion procedures; Integrin alpha4beta1; JAK1 gene; JAK2 gene; Malignant Neoplasms; Marrow; Methods; Monoclonal Antibodies; Natural Killer Cells; Natural regeneration; Patients; Phase I Clinical Trials; Pre-Clinical Model; Progressive Disease; Reagent; Recurrence; Refractory; Relapse; Research; Signal Pathway; System; T-Lymphocyte; Testing; Time; Translating; Vascular Cell Adhesion Molecule-1; acute myeloid leukemia cell; base; bench to bedside; cancer genomics; career; chemotherapy; chimeric antigen receptor T cells; curative treatments; design; early phase clinical trial; efficacy testing; first-in-human; graft vs host disease; graft vs leukemia effect; inhibitor/antagonist; leukemia; novel; preclinical study; prevent; programs; success; targeted treatment

PROJECT SUMMARY/ABSTRACT Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only curative therapy for many patients with hematologic malignancies and marrow failure states. Key obstacles to the success of HSCT include collecting optimal numbers of hematopoietic stem/progenitor cells (HSPCs) capable of multilineage and durable engraftment, control of graft-versus-host disease (GvHD), and treating disease recurrence both before and especially after HSCT. I have focused my career over the last 20 years on overcoming these three obstacles to HSCT through the use of a bench-to-bedside and back again research approach. My research program over the next seven years will use our strengths in preclinical modeling, cancer genomics and the design and execution of early phase clinical trials to (1) develop novel methods to target the hematopoietic niche for optimal HSPC mobilization and chemosensitization of acute myeloid leukemia (AML), (2) target the interferon gamma receptor (IFNγR) and IL-6R signaling pathways via use of selective and balanced JAK1/2 inhibitors to mitigate GvHD while maintaining graft vs. leukemia (GvL) after allo-HSCT, and (3) design and test novel AML and T cell acute lymphoblastic leukemia (T-ALL) immunotherapeutics. Successful HSCT requires the infusion of a sufficient number of HSPCs that are capable of homing to the bone marrow cavity and regenerating durable trilineage hematopoiesis in a timely fashion. In our first research area, we will use new strategies to enhance HSPC mobilization and leukemia chemosensitization via targeted modulation of the CXCR4/CXCL12, VLA-4/VCAM-1 and/or CXCR2/Gro- axes. Managing the threat of GvHD while maximizing the beneficial GvL effect would broaden the scope and usefulness of allo-HSCT. In our second major research area we will perform preclinical and clinical studies to determine if targeting IFNγR, IL-6R, and/or JAK1/JAK2 can mitigate GvHD while maintaining GvL after T cell replete allo-HSCT. Finally, since many patients with AML die from progressive disease after relapse, our third research area will develop and translate into early phase clinical trials novel bi- and tri-specific monoclonal antibody reagents for the treatment of AML relapse before and after HSCT. We will complete “first-in-man” phase I clinical trials of MGD006, a CD123xCD3 Dual Affinity Re-Targeting (DART) bispecific antibody-based molecule and AMV564, a CD33xCD3 Tandem Diabody, in patients with relapsed/refractory AML. While these trials are ongoing we are identifying novel targets for immunotherapy in AML and testing the efficacy of new retargeting agents that engage either T cells, NK cells or other immune effector cells to kill AML blasts expressing CD123, CD33, or the novel targets. Finally, since no targeted therapies currently exist for T-ALL, we are developing allogeneic chimeric antigen receptor T cells (CAR-T) to CD7, a T and NK cell marker that is highly expressed in T cell malignancies and in up to 40% of AML cases. To prevent normal T cell fratricide and alloreactivity, we are using the CRISPR/Cas-9 system to delete CD7 and the TCR chain from donor T cells prior to transduction with the CD7 CAR.

项目总结/摘要 异基因造血干细胞移植（allo-HSCT）仍然是许多患者唯一的治愈性治疗方法 患有恶性血液病和骨髓衰竭HSCT成功的主要障碍包括 收集最佳数量的能够多谱系的造血干/祖细胞（HSPC）， 持久的植入，控制移植物抗宿主病（GvHD），治疗疾病复发， 尤其是HSCT后在过去的20年里，我的职业生涯一直专注于克服这三个问题。 HSCT的障碍，通过使用一个实验室到床边，再回来的研究方法。我的研究 在未来七年的计划将利用我们在临床前建模，癌症基因组学和 设计和执行早期临床试验，以（1）开发靶向造血干细胞的新方法， 最佳HSPC动员和急性髓性白血病（AML）化疗增敏的利基，（2）靶向 干扰素γ受体（IFNγR）和IL-6 R信号通路通过使用选择性和平衡JAK 1/2 抑制剂，以减轻GvHD，同时维持allo-HSCT后移植物抗白血病（GvL），和（3）设计和测试 新的AML和T细胞急性淋巴细胞白血病（T-ALL）免疫治疗剂。成功的HSCT需要 输注足够数量的能够归巢至骨髓腔的HSPC， 及时再生持久的三系造血。在第一个研究领域，我们将使用新的 通过靶向调节HSPC动员和白血病化疗增敏的策略 CXCR 4/CXCL 12、VLA-4/VCAM-1和/或CXCR 2/GRO-1轴。管理GvHD的威胁，同时最大限度地 有益的GvL效应将拓宽allo-HSCT的范围和有用性。在我们的第二个主要研究中， 我们将进行临床前和临床研究，以确定是否靶向IFNγR，IL-6 R和/或JAK 1/JAK 2， 在T细胞充满的allo-HSCT后，可以减轻GvHD，同时维持GvL。最后，由于许多AML患者 复发后死于疾病进展，我们的第三个研究领域将发展并转化为早期阶段 临床试验新型双特异性和三特异性单克隆抗体试剂用于治疗AML复发前 HSCT后。我们将完成MGD 006的“首次人体”I期临床试验，MGD 006是一种CD 123 xCD 3双亲和药物， 基于再靶向（DART）双特异性抗体的分子和AMV 564（一种CD 33 xCD 3串联双抗体）， 复发性/难治性AML患者。虽然这些试验正在进行中，我们正在确定新的目标， AML的免疫治疗，并测试新的重靶向药物的疗效， 或其它免疫效应细胞以杀死表达CD 123、CD 33或新靶点的AML母细胞。最后，由于 目前还没有针对T-ALL的靶向治疗，我们正在开发同种异体嵌合抗原受体T细胞 CD 7是一种T细胞和NK细胞标志物，在T细胞恶性肿瘤中高度表达，在高达40%的 AML病例。为了防止正常的T细胞自相残杀和同种异体反应性，我们正在使用CRISPR/Cas-9系统， 在用CD 7 CAR转导之前从供体T细胞中删除CD 7和TCR γ链。