RETARGETING AGENTS TO TREAT AML

 描述（由申请人提供）：本研究的目的是开发用于治疗急性髓性白血病（AML）的新型免疫治疗药物并将其转化为早期临床试验。不到一半的AML患者通过目前的治疗方法治愈，并且不适合造血干细胞移植（HSCT）的复发性和难治性AML患者没有治愈性治疗选择。与同基因或自体移植相比，异基因HSCT后复发率降低，免疫系统在控制和根除白血病中的作用是显而易见的。由于同种异体HSCT与显著的发病率和死亡率相关，因此开发替代疗法非常重要。 AML的免疫疗法。我们将研究AML的新免疫治疗方法，具体目标如下：目标1：在高危AML患者中进行MGD 006（一种基于CD 123 × CD 3双亲和再靶向（DART）双特异性抗体的分子）的“首次人体”I期临床试验。本研究设计为三个部分：单个患者剂量递增部分，随后是多患者剂量递增部分，最后是最大耐受剂量和时间表扩展部分。目的2：我们将表征MGD 006在AML患者中的免疫调节活性和潜在抗肿瘤活性。将分析目标1中获得的相关研究样品的（i.）血清细胞因子，（ii.）AML和T细胞亚群数量、表型和功能，以及（iii.）AML母细胞和T细胞的亚克隆结构。目标3：我们将确定人类AML免疫治疗的新靶点，并测试新的重靶向药物杀死表达CD 123或这些新靶点的AML原始细胞的疗效。我们将使用库存的AML和正常的CD 34+干细胞来鉴定AML中差异表达的表面蛋白。我们还将检查替代重靶向剂（CD 123 xCD 16、CD 123 xCD 47和CD 123 xCD 3xPD 1）和效应细胞（静息和CIML-NK细胞）在杀伤白血病原始细胞方面的疗效。如果我们的MGD 006 I期临床试验显示出良好的安全性特征，在被认为预后不良的患者中具有明确和有意义的疗效体征，我们将在II期试验中进一步研究该方法。我们在Aim 3中的研究将试图鉴定AML细胞上的新抗原，并开发替代的重靶向剂，其参与T细胞、NK细胞或其他免疫效应细胞。

 DESCRIPTION (provided by applicant): The objective of this research is to develop and translate into early phase clinical trials novel immunotherapeutics for the treatment of Acute Myelogenous Leukemia (AML). Less than half of AML patients are cured with current treatment approaches, and relapse and refractory AML patients who are not candidates for hematopoietic stem cell transplantation (HSCT) have no curative treatment options. The role of the immune system in the control and eradication of leukemia is evident in the reduced relapse rate after allogeneic HSCT compared with syngeneic or autologous transplantation. Since allogeneic HSCT is associated with significant morbidity and mortality, it is important to develop alternative immunotherapies for AML. We will investigate novel immunotherapeutic approaches for AML in the following specific aims: Aim 1: To conduct a "first-in-human" Phase I clinical trial of MGD006, a CD123×CD3 Dual Affinity Re-Targeting (DART) bi-specific antibody-based molecule, in patients with high risk AML. This study is designed in three segments: a Single Patient Dose Escalation segment, followed by a Multi-Patient Dose Escalation segment and finally a Maximum Tolerated Dose and Schedule expansion segment. Aim 2: We will characterize the immunomodulatory activity and potential anti- tumor activity of MGD006 in patients with AML. Correlative study samples obtained in Aim 1 will be analyzed for (i.) serum cytokines, (ii.) AML and T cell subset numbers, phenotype and function and (iii.) the sub clonal architecture of AML blasts and T cells. Aim 3: We will identify novel targets for immunotherapy in human AML and test the efficacy of new retargeting agents to kill AML blasts expressing CD123 or these novel targets. We will use banked AML and normal CD34+ stem cells to identify differentially expressed surface proteins in AML. We will also examine alternative retargeting agents (CD123xCD16, CD123xCD47, and CD123xCD3xPD1) and effector cells (resting and CIML-NK cells) for their efficacy in killing leukemic blasts. If our phase 1 clinical trial with MGD006 shows a good safety profile with clear and meaningful signs of efficacy in patients deemed to have a poor prognosis, we will pursue further investigation of the approach in a phase 2 trial. Our studies in Aim 3 will attempt to identify novel antigens on AML cells and develop alternative retargeting agents that engage either T cells, NK cells or other immune effector cells.