Chimeric Antigen Receptor T cell Therapy for Acute Myeloid Leukemia (AML)

嵌合抗原受体 T 细胞疗法治疗急性髓系白血病 (AML)

基本信息

批准号：
8869912
负责人：
Saar Gill
金额：
$ 16.78万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8869912
关键词：
Ablation Acute Myelocytic Leukemia Address Allogenic Antibodies Antigens Award B lymphoid malignancy B-Lymphocytes Binding Bioinformatics Blood CD19 gene Cell Therapy Cell surface Cells Chronic Lymphocytic Leukemia Clinical Clinical Sciences Clinical Trials Data Development Disease remission Disease-Free Survival Eligibility Determination Ensure Funding Genetic Engineering Gills Goals Health Hematologic Neoplasms Hematopoietic Stem Cell Transplantation IL3RA gene Immunotherapeutic agent Immunotherapy Knowledge Malignant Neoplasms Marrow Mass Spectrum Analysis Membrane Membrane Proteins Mentors Mission Modality Molecular Biology Morbidity - disease rate Normal tissue morphology Patients Pennsylvania Physicians Pre-Clinical Model Proteomics Public Health Publishing Refractory Regimen Research Research Activity Safety Scientist Signal Transduction Specificity Stem cells Surface Antigens T cell therapy T-Lymphocyte Testing Therapeutic Tissues Toxic effect Training Training and Education Translating Translational Research Universities Work base cancer therapy chemotherapy chimeric antigen receptor combinatorial conditioning design experience hematopoietic cell transplantation innovation leukemia mortality novel novel strategies oncology pre-clinical response skills stem success tumor

项目摘要

DESCRIPTION (provided by applicant): With rare exceptions, the treatment for acute myeloid leukemia (AML) has changed little in the last 40 years and long-term overall survival has remained stable at approximately 30%. The group directed by the applicant's mentor, Dr Carl June, is recognized as a world leader in the field of genetically-engineered T cell therapy for hematologic malignancy, with well- publicized recent success in treating CD19+ B-cell leukemias. In part, the success of this therapy depends on the restricted tissue expression of CD19 and on the ability of patients to tolerate prolonged depletion of normal B cells. In contrast to B-cell leukemias, AML presents a unique set of challenges, as it is fundamentally a cancer of hematopoietic stem/progenitor cells. Therefore, the underlying challenge limiting the application of powerful immunotherapy approaches to AML is the lack of truly leukemia-specific antigens. The long-term goal of this research is to apply the CAR-T cell approach to AML. The overall objective as the next step in pursuit of the above goal is to identify safe ways to treat AML without endangering normal tissue. The central hypothesis is that careful selection of target-specific CAR constructs, either singly or in combination, can maximize on-target efficacy while minimizing the consequences of off-target toxicity. Guided by strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) design of split-signaling CAR constructs wherein activation is conditional upon the T cell encountering two antigens, thus increasing the specificity of CAR stimulation; 2) demonstration that the myeloablative off-tumor effect of CAR-T cells can be harnessed as a novel cellular conditioning regimen for HCT; and 3) identification of novel cell-surface targets in AML using proteomics followed by bioinformatics analysis. The approach is innovative, in the applicant's opinion, as it departs from the status quo by extending both the range of available AML targets using novel approaches to target discovery, as well as the utility of existing AML targets using conditional expressing CAR constructs. The proposed research is significant, because it will contribute depth (of clinical responses) and breadth (of eligibility for potentially curative therapy) to the therapeutic arsenal against AML. Ultimately, such knowledge has the potential to vertically advance the burgeoning field of chimeric antigen receptor-redirected T cell immunotherapy in AML and other malignancies. The proposed research activities are crucial to the development of the applicant as an independently-funded physician-scientist with a focus on cellular immunotherapy. Dr Gill will receive further training in molecular biology from his mentor Dr Carl June, and training in proteomics and in bioinformatics from experienced collaborators at the University of Pennsylvania. Therefore at the conclusion of the training period, the applicant will have acquired a unique set of intellectual and technical skills that will allow him to attack the problem of AML- specific immunotherapeutics from several angles at once. In addition, this award will support a unique training experience in translational research and will establish an academic path- way for the discovery and development of new chimeric antigen receptor T cell approaches.

描述（由申请人提供）：除了极少数例外，急性髓系白血病 (AML) 的治疗在过去 40 年中几乎没有变化，长期总体生存率稳定在 30% 左右。 Carl June 博士被公认为血液恶性肿瘤基因工程 T 细胞治疗领域的世界领先者，最近在治疗 CD19+ B 细胞方面取得了广为人知的成功在某种程度上，这种疗法的成功取决于 CD19 的组织表达以及患者耐受正常 B 细胞长期耗竭的能力。与 B 细胞白血病相比，AML 面临着一系列独特的挑战。本质上是一种造血干细胞/祖细胞癌症，因此，限制针对 AML 的强大免疫治疗方法的应用的根本挑战是缺乏真正的白血病特异性抗原。将 CAR-T 细胞方法应用于 AML 的总体目标是找到治疗 AML 且不危及正常组织的安全方法。无论是强烈的还是联合的，都可以最大限度地提高单靶点功效，同时最大限度地减少脱靶毒性的后果。在强有力的初步数据的指导下，这一假设将通过追求三个具体目标进行检验：1）设计分裂信号 CAR 结构，从而激活。是有条件的T 细胞遇到两种抗原，从而增加 CAR 刺激的特异性；2) 证明 CAR-T 细胞的清髓性非肿瘤效应可用作 HCT 的新型细胞调理方案；3) 鉴定新型细胞申请人认为，该方法是创新的，因为它脱离了现状。通过使用新的靶标发现方法扩展可用的 AML 靶标的范围，以及使用条件表达 CAR 构建体的现有 AML 靶标的效用，拟议的研究意义重大，因为它将贡献（临床反应的）深度和广度。潜在治愈性治疗的资格）到治疗库最终，这些知识有可能垂直推进嵌合抗原受体重定向 T 细胞免疫疗法在 AML 和其他恶性肿瘤中的新兴领域。拟议的研究活动对于申请人作为一名独立资助的医师科学家的发展至关重要。吉尔博士将专注于细胞免疫疗法，并将接受其导师卡尔·琼博士的进一步分子生物学培训，并接受宾夕法尼亚大学经验丰富的合作者的蛋白质组学和生物信息学培训。在培训期间，申请人将获得一套独特的知识和技术技能，这将使他能够解决反洗钱问题此外，该奖项还将支持转化研究方面的独特培训经验，并将为发现和开发新的嵌合抗原受体 T 细胞方法建立学术途径。