RETARGETING AGENTS TO TREAT AML

 描述(申请人提供)：这项研究的目标是开发治疗急性髓系白血病(AML)的新型免疫疗法并将其转化为早期临床试验。只有不到一半的AML患者可以用目前的治疗方法治愈，而复发和难治性的AML患者不是造血干细胞移植(HSCT)的候选对象，没有治愈的治疗选择。与同基因或自体移植相比，异基因造血干细胞移植后复发率降低，说明免疫系统在控制和根除白血病方面的作用是显而易见的。由于异基因造血干细胞移植与显著的发病率和死亡率有关，因此开发替代方案很重要。 急性髓系白血病的免疫疗法。我们将在以下特定目标中探索治疗AML的新的免疫治疗方法：目的1：在高危AML患者中进行MGD006(一种CD123×CD3双亲和重靶向(DART)双特异性抗体分子)的第一阶段临床试验。这项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计划扩展部分。目的：研究MGD006在急性髓系白血病(AML)患者中的免疫调节活性和潜在的抗肿瘤活性。在目标1中获得的相关研究样本将被分析(i.)血清细胞因子，(Ii)AML和T细胞亚群数量、表型和功能及(Iii)AML原始细胞和T细胞的亚克隆构筑。目的3：我们将在人类AML中寻找新的免疫治疗靶点，并测试新的重定向药物对表达CD123或这些新靶点的AML细胞的杀伤效果。我们将使用储存的AML和正常的CD34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定向剂(CD123xCD16、CD123xCD47和CD123xCD3xPD1)和效应细胞(静息和CIML-NK细胞)在杀死白血病原始细胞方面的有效性。如果我们使用MGD006进行的第一阶段临床试验显示，对于被认为预后较差的患者具有良好的安全性和明确而有意义的疗效迹象，我们将在第二阶段试验中对该方法进行进一步研究。我们在AIM 3中的研究将尝试识别AML细胞上的新抗原，并开发可与T细胞、NK细胞或其他免疫效应细胞结合的替代重定向药物。

 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.