BM NICHE DISRUPTION AND IMMUNOTHERAPY IN HEMATOLOGICAL MALIGNANCIES

摘要 造血干细胞移植(HSCT)仍然是许多慢性粒细胞白血病患者的唯一治疗方法。 恶性血液病和骨髓衰竭状态。HSCT成功的关键障碍包括收集 能够多系和持久植入的最佳造血干细胞数量，移植物的控制- 抗宿主病(GvHD)和治疗HSCT前后的疾病复发。Dr。 在过去的20年里，迪佩西奥的职业生涯致力于克服HSCT的这三个障碍 使用了从床到床，然后再回来的研究方法。我有幸花了我全部的时间 与DiPersio博士一起工作了15年的研究生研究生涯。在这段时间里，我贡献了16个 DiPersio博士的同行评审手稿，完成了4个项目的临床前研究，这些项目导致了第一个- 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名技术人员 并对涉及400多名患者的17项不同临床试验进行了相关研究。迪佩西奥医生的 未来几年的研究计划将利用我们在临床前建模、癌症基因组学方面的优势 以及早期临床试验的设计和实施，以1)开发新的和高度临床相关的 方法以造血细胞为靶点，最佳动员造血干细胞和化疗药物。 急性髓系白血病(AML)和多发性骨髓瘤的纳米颗粒致敏；2)基因特征 异基因造血干细胞移植后AML复发的表观遗传学改变 (AllHSCT)；以及3)设计和测试新的AML免疫疗法，以降低AML在或之前复发的风险 HSCT后。成功的造血干细胞移植需要输注足够数量的造血干细胞 能及时归巢至骨髓腔，再生耐久的三系造血 时尚。在我们的第一个研究领域，我们将使用多种策略来加强干细胞动员和 靶向调控CXCR4/CXCL12、VLA-2对白血病的化学和纳米颗粒增敏作用 4/VCAM-1和CXCR2/CXCL1-7轴。在我们的第二个主要研究领域，我们将确定基因变化 这导致人类和小鼠异基因造血干细胞移植后AML复发。最后，由于大多数急性髓系白血病患者死于 进展性疾病复发后，我们的第三个研究领域将发展并转化为早期临床 新型双特异性和三特异性单抗试剂治疗急性髓系白血病复发前后的试验 HSCT。我们将完成CD123×CD3双重亲和力的MGD006的第一阶段临床试验。 靶向(DART)基于双特异性抗体的分子，用于复发/难治性AML患者。虽然这场审判 我们正在为急性髓细胞白血病的免疫治疗寻找新的靶点，并测试新的 与T细胞、NK细胞或其他免疫效应细胞结合以杀死AML原始细胞的重定向药物 表达CD123或新的靶点。我既是一名基础研究人员，也是一名监督人员，以完成 迪佩西奥博士癌症研究项目的目标。

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.