RETARGETING AGENTS TO TREAT AML

重新定位药物治疗 AML

基本信息

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
项目类别：
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

项目摘要

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）的新型免疫疗法并将其转化为早期临床试验，只有不到一半的 AML 患者能够通过当前的治疗方法治愈并复发。不适合接受造血干细胞移植（HSCT）的难治性 AML 患者没有治愈性治疗选择。免疫系统在控制和根除白血病中的作用。与同基因或自体移植相比，同种异体 HSCT 后的复发率明显降低，因为同种异体 HSCT 与显着的发病率和死亡率相关，因此开发替代疗法非常重要。我们将研究针对 AML 的新型免疫治疗方法，具体目标如下：目标 1：进行 MGD006（CD123×CD3 双重亲和力重新靶向（DART））的“首次人体”I 期临床试验。基于双特异性抗体的分子，用于高危 AML 患者这项研究分为三个部分：单患者剂量递增部分，然后是多患者剂量递增部分。剂量递增部分以及最后的最大耐受剂量和时间表扩展部分目标 2：我们将分析目标 1 中获得的相关研究样本的 MGD006 的免疫调节活性和潜在抗肿瘤活性。 ) 血清细胞因子，(ii.) AML 和 T 细胞数量子集、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：我们将鉴定新的。我们将使用储存的 AML 和正常 CD34+ 干细胞来鉴定 AML 中差异表达的表面蛋白。药物（CD123xCD16、CD123xCD47 和 CD123xCD3xPD1）和效应细胞（静息细胞和 CIML-NK 细胞）在如果我们的 MGD006 1 期临床试验显示出良好的安全性，并且对预后不良的患者具有明确且有意义的疗效迹象，我们将在 2 期试验中进一步研究该方法。目标 3 将尝试识别 AML 细胞上的新抗原，并开发与 T 细胞、NK 细胞或其他免疫效应细胞结合的替代重定向剂。