Optimizing Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Malignancies

项目摘要/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。 患有恶性血液病和骨髓衰竭。HSCT成功的主要障碍包括 收集最佳数量的具有多系和多向分化能力的造血干/祖细胞 耐久植入、控制移植物抗宿主病(GvHD)和治疗疾病复发 尤其是在HSCT之后。在过去的20年里，我一直致力于克服这三个问题 通过使用长凳到床边然后再回来的研究方法来阻碍HSCT。我的研究 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 设计和实施早期临床试验，以(1)开发以造血为靶点的新方法 优化HSPC动员和化疗增敏急性髓系白血病(AML)的利基，(2)靶向 干扰素γ受体和IL-6R信号通路的选择性和平衡性 在维持异基因造血干细胞移植后移植物抗白血病(GVL)的同时缓解GvHD的抑制剂，以及(3)设计和试验 新的AML和T细胞急性淋巴细胞白血病(T-ALL)免疫疗法。成功的HSCT需要 输注足够数量的能够回到骨髓腔的HSPC，并 及时再生耐用的三联造血。在我们的第一个研究领域，我们将使用新的 靶向调控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。管理GvHD威胁，同时最大限度地 有益的GVL效应将扩大allo-HSCT的范围和用途。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，以确定是否针对干扰素γR、IL-6R和/或JAK1/JAK2 能减轻移植物抗宿主病，同时维持T细胞完全移植后的移植物抗宿主病。最后，由于许多急性髓系白血病患者 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抗试剂治疗AML复发的临床试验 和HSCT后。我们将完成CD123xCD3双亲和物MGD006的第一阶段临床试验 重靶向(DART)双特异性抗体分子和AMV564，CD33xCD3串联Diabody，在 复发/难治性AML患者。虽然这些试验仍在进行中，但我们正在确定新的目标 急性髓系白血病的免疫治疗和检测T细胞、NK细胞结合的新型重定向药物的疗效 或其他免疫效应细胞杀伤表达CD123、CD33或新靶点的AML细胞。最后，既然 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 (CAR-T)到CD7，一种T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 急性髓系白血病病例。为了防止正常的T细胞杀伤和同种异体反应，我们正在使用CRISPR/Cas-9系统来 在CD7CAR转导前，从供者T细胞中删除CD7和TcR链。

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.