BM NICHE DISRUPTION AND IMMUNOTHERAPY IN HEMATOLOGICAL MALIGNANCIES

血液系统恶性肿瘤中的 BM 生态位破坏和免疫治疗

• 批准号: 9767584
• 负责人: Michael Rettig
• 金额: $ 17.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767584
• 关键词: Acute Myelocytic Leukemia; Affinity; Allogenic; Area; Back; Bispecific Antibodies; Bone Marrow; CD3 Antigens; CXCL1 gene; CXCL12 gene; CXCR4 gene; Cancer Research Project; Clinical Trials; Correlative Study; Disease; Effector Cell; Engraftment; Epigenetic Process; Failure; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homing; IL3RA gene; IL8RB gene; Immune; Immunotherapeutic agent; Immunotherapy; Infusion procedures; Integrin alpha4beta1; Leukemic Cell; Manuscripts; Marrow; Methods; Monoclonal Antibodies; Multiple Myeloma; Mus; Mutation; Natural Killer Cells; Natural regeneration; Patients; Peer Review; Phase; Phase I Clinical Trials; Post Graduate Year; Postdoctoral Fellow; Pre-Clinical Model; Progressive Disease; Reagent; Recurrence; Refractory; Relapse; Research; Research Personnel; Risk; Supervision; T-Lymphocyte; Testing; Time; Training; Translating; Vascular Cell Adhesion Molecule-1; base; bench to bedside; cancer genomics; career; clinically relevant; curative treatments; design; efficacy testing; first-in-human; graft vs host disease; leukemia; man; nanoparticle; nanotherapeutic; novel; preclinical study; programs; success

Abstract Hematopoietic stem cell transplant (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 cells capable of multilineage and durable engraftment, control of graft- versus-host disease (GvHD) and treating disease recurrence both before and especially after HSCT. Dr. DiPersio has focused his 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. I have been fortunate to spend my entire 15-year post-graduate research career working with Dr. DiPersio. During this time, I have contributed to 16 of Dr. DiPersio's peer-reviewed manuscripts, completed pre-clinical studies for 4 projects that led to first-in- human clinical trials, assisted in the training of 9 post-docs and/or fellows, trained and supervised 4 technicians and performed correlative studies for 17 different clinical trials involving over 400 patients. Dr. DiPersio's research program over the next several years will use our strengths in preclinical modeling, cancer genomics and the design and execution of early phase clinical trials to 1) develop novel and highly clinically relevant methods to target the hematopoietic niche for optimal mobilization of hematopoietic stem cells and chemo- and nanoparticle-sensitization of acute myeloid leukemia (AML) and multiple myeloma; 2) characterize the genetic and epigenetic changes that contribute to AML relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT); and 3) design and test novel AML immunotherapeutics to reduce the risk of AML relapse before or after HSCT. Successful HSCT requires the infusion of a sufficient number of hematopoietic stem cells 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 multiple strategies to enhance stem cell mobilization and leukemia chemo- and nanoparticle-sensitization via targeted modulation of the CXCR4/CXCL12, VLA- 4/VCAM-1 and CXCR2/CXCL1-7 axes. In our second major research area we will identify the genetic changes that contribute to AML relapse after alloHSCT in man and mice. Finally, since most 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 a “first-in-man” phase I clinical trial of MGD006, a CD123×CD3 Dual Affinity Re- Targeting (DART) bispecific antibody-based molecule, in patients with relapsed/refractory AML. While this trial is 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 or the novel targets. I serve as both a basic researcher and supervisor to accomplish the goals of Dr. DiPersio's cancer research program.

摘要 造血干细胞移植（HSCT）仍然是许多患者的唯一治愈性疗法， 血液恶性肿瘤和骨髓衰竭状态。HSCT成功的关键障碍包括收集 最佳数量的造血干细胞能够多谱系和持久的植入，控制移植物， 抗宿主病（GvHD）和治疗HSCT之前和之后的疾病复发。博士 在过去的20年里，DiPersio一直专注于克服HSCT的这三个障碍， 使用从实验室到床边再返回的研究方法。我很幸运能把我的整个 15-一年的研究生研究生涯与DiPersio博士一起工作。在这段时间里，我为16个 博士DiPersio的同行评审手稿，完成了4个项目的临床前研究，导致首次在 人体临床试验，协助培训9名博士后和（或）研究员，培训和监督4名技术员 并对17个不同的临床试验进行了相关研究，涉及400多名患者。DiPersio医生的 未来几年的研究计划将利用我们在临床前建模、癌症基因组学 以及设计和执行早期临床试验，以1）开发新的和高度临床相关的 靶向造血小生境以最佳动员造血干细胞和化疗的方法 急性髓性白血病（AML）和多发性骨髓瘤的纳米颗粒致敏; 2）表征遗传 异基因造血干细胞移植后导致AML复发的表观遗传学变化 （alloHSCT）;和3）设计和测试新的AML免疫治疗剂以降低AML复发的风险， HSCT后成功的HSCT需要输注足够数量的造血干细胞， 能够及时归巢到骨髓腔，再生持久的三系造血， 时尚.在我们的第一个研究领域，我们将使用多种策略来增强干细胞动员， 通过靶向调节CXCR 4/CXCL 12、VLA- 4/VCAM-1和CXCR 2/CXCL 1 -7轴。在我们的第二个主要研究领域，我们将确定遗传变化， 导致人类和小鼠alloHSCT后AML复发。最后，由于大多数AML患者死于 复发后疾病进展，我们的第三个研究领域将发展并转化为早期临床 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复发前后 HSCT。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 × CD 3双亲和抗体， 靶向（DART）双特异性抗体为基础的分子，在复发性/难治性AML患者。虽然这次审判 正在进行中，我们正在确定AML免疫治疗的新靶点，并测试新靶点的疗效。 重靶向药物，其与T细胞、NK细胞或其他免疫效应细胞结合以杀死AML原始细胞 表达CD 123或新靶点。我作为一个基础研究员和监督员来完成 DiPersio博士癌症研究计划的目标。