RETARGETING AGENTS TO TREAT AML

重新定位药物治疗 AML

• 批准号: 8864581
• 负责人: John F. Dipersio
• 金额: $ 38.01万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8864581
• 关键词: Acute Myelocytic Leukemia; Affinity; Allogenic; Antibodies; Antigens; Apoptosis; Architecture; Autologous Transplantation; B lymphoid malignancy; Bispecific Antibodies; Blast Cell; Bone Marrow; CD3 Antigens; CD34 gene; CD47 gene; Candidate Disease Gene; Cell Line; Cell surface; Cells; Clinical Trials; Correlative Study; Cytotoxic T-Lymphocytes; Cytotoxic agent; Development; Diagnostic; Disease; Disease remission; Disease-Free Survival; Dose; Dose-Limiting; Drug Kinetics; Effector Cell; FCGR3B gene; Hematopoietic; Hematopoietic Stem Cell Transplantation; Human; IL3RA gene; Immune; Immune system; Immunologics; Immunotherapeutic agent; Immunotherapy; Investigation; Isogenic transplantation; Maximum Tolerated Dose; Mediating; Membrane Proteins; Modeling; Morbidity - disease rate; Mus; Natural Killer Cells; Outcome; Partial Remission; Patients; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Population; Pre-Clinical Model; Production; Progressive Disease; Proteins; Reagent; Refractory; Relapse; Research; Rest; Role; Safety; Sampling; Schedule; Serum; Stem cells; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Toxic effect; Translating; Treatment Failure; base; cancer cell; chemotherapy; comparative efficacy; cytokine; design; differential expression; efficacy testing; exome sequencing; high risk; human IL3RA protein; immunogenicity; improved; in vivo; killings; leukemia; leukemic stem cell; macrophage; mortality; neoplastic cell; next generation; novel; outcome forecast; overexpression; peripheral blood; public health relevance; response; stem; tumor

 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.

 描述（由适用提供）：这项研究的目的是开发并转化为早期临床试验，用于治疗急性骨髓性白血病（AML）的新型免疫治疗药。不到一半的AML患者使用当前的治疗方法治愈，而不是造血干细胞移植（HSCT）的候选者的缓解和难治性的AML患者没有治疗方法。自同种异体HSCT以来的作用与明显的发病率和死亡率有关，很重要的是开发替代方案 AML的免疫疗法。我们将在以下特定目的中研究AML的新型免疫疗法方法：目标1：对MGD006进行“第一阶段” I期临床试验，这是一种CD123×CD3双重亲和力重新靶向（DART）基于双重风险AML的患者的基于双特异性抗体分子。这项研究是在三个部分中设计的：一个单个患者剂量升级部分，其次是多患者剂量升级段，最后是最大耐受剂量和计划膨胀段。 AIM 2：我们将表征AML患者MGD006的免疫调节活性和潜在的抗肿瘤活性。在AIM 1中获得的相关研究样本将分析（i。）血清细胞因子，（ii。）AML和T细胞子群数，表型和功能以及（iii。）AML Blasts和T细胞的亚克隆结构。 AIM 3：我们将确定人AML中免疫疗法的新型靶标，并测试新的重新定位剂杀死表达CD123或这些新靶标的AML爆炸的有效性。我们将使用银行AML和正常的CD34+干细胞来识别AML中不同表达的表面蛋白。我们还将检查替代的重新定位剂（CD123XCD16，CD123XCD47和CD123XCD3XPD1）和效应细胞（静止和CIML-NK细胞）在杀死白血病爆炸方面的有效性。如果我们使用MGD006的1阶段临床试验显示出良好的安全性，并且在被认为预后不良的患者中具有明确而有意义的有效性迹象，我们将在第二阶段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细胞上的新型抗原，并开发替代T细胞，NK细胞或其他免疫效应细胞的替代重定位剂。