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.

项目概要/摘要 异基因造血干细胞移植（allo-HSCT）仍然是许多患者的唯一治疗方法 造血干细胞移植成功的主要障碍包括血液系统恶性肿瘤和骨髓衰竭状态。 收集最佳数量的能够进行多谱系和分化的造血干细胞/祖细胞 (HSPC) 持久植入、控制移植物抗宿主病 (GvHD) 以及治疗之前的疾病复发 尤其是在 HSCT 之后，我在过去 20 年的职业生涯中一直致力于克服这三个问题。 我的研究通过使用从实验室到临床再返回的研究方法来克服 HSCT 的障碍。 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) 开发针对造血功能的新方法 急性髓系白血病 (AML) 最佳 HSPC 动员和化疗增敏的利基，(2) 通过使用选择性和平衡的 JAK1/2 干扰素 γ 受体 (IFNγR) 和 IL-6R 信号通路 在allo-HSCT后减轻GvHD同时维持移植物抗白血病（GvL）的抑制剂，以及（3）设计和测试 新型 AML 和 T 细胞急性淋巴细胞白血病 (T-ALL) 免疫疗法需要成功的 HSCT。 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功能在我们的第一个研究领域，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 CXCR4/CXCL12、VLA-4/VCAM-1 和/或 CXCR2/Gro- 轴，同时最大限度地管理 GvHD 的威胁。 在我们的第二个主要研究中，有益的 GvL 效应将扩大异基因造血干细胞移植的范围和用途。 我们将在该领域进行临床前和临床研究，以确定是否针对 IFNγR、IL-6R 和/或 JAK1/JAK2 最后，由于许多患有 AML 的患者，在 T 细胞充满异基因造血干细胞移植后可以减轻 GvHD，同时维持 GvL。 复发后死于进展性疾病，我们的第三个研究领域将发展并转化为早期阶段 新型双特异性和三特异性单克隆抗体试剂治疗 AML 复发的临床试验 HSCT之后，我们将完成MGD006（一种CD123xCD3双重亲和力）的“首次人体”I期临床试验。 基于重新靶向 (DART) 双特异性抗体的分子和 AMV564（一种 CD33xCD3 串联双抗体） 在这些试验正在进行的同时，我们正在寻找新的治疗靶点。 AML 免疫疗法并测试与 T 细胞、NK 细胞结合的新型重定向药物的功效 或其他免疫效应细胞来杀死表达 CD123、CD33 或新靶点的 AML 母细胞。 目前尚无针对T-ALL的靶向疗法，我们正在开发同种异体嵌合抗原受体T细胞 (CAR-T) 转化为 CD7，CD7 是一种 T 细胞和 NK 细胞标记物，在 T 细胞恶性肿瘤和高达 40% 的肿瘤中高度表达。 为了防止正常 T 细胞自相残杀和同种异体反应，我们使用 CRISPR/Cas-9 系统来预防 AML 病例。 在用 CD7 CAR 转导之前，从供体 T 细胞中删除 CD7 和 TCRα 链。