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：
9061647
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/9061647
关键词：
Ablation Acute Myelocytic Leukemia Address Allogenic Antibodies Antigens Award B lymphoid malignancy B-Cell Leukemia B-Lymphocytes Binding Bioinformatics Blood CD19 gene Cell Therapy Cell surface Cells 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 Technical Expertise Testing Therapeutic Tissues Toxic effect Training Training and Education Translating Translational Research Universities Work base cancer therapy chemotherapy chimeric antigen receptor combinatorial conditioning curative treatments design experience hematopoietic cell transplantation innovation leukemia mortality novel novel strategies oncology pre-clinical response 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（通过应用程序证明）：除了极少数例外，急性髓样白血病（AML）的治疗在过去40个长期的总生存期间几乎没有变化，使该小组导演的导师Carl June恢复了稳定。被认为是遗传引擎T细胞治疗领域的世界领导者，用于治疗CD19+ B细胞白血病的成功，部分是CD19的成功。正常的B细胞。从根本上讲，它是造血茎/祖细胞的癌症。 AML的T细胞方法。关闭。新的调理方案用于HCT和3）使用蛋白质组学中的Novel细胞表面靶标，然后是生物信息分析。通过使用新颖的方法扩展两种目标，以发现拟议的表达汽车构建体。反对AML，最终，在AML的其他恶性肿瘤中，嵌合抗原的迅速发展的潜力对于申请人的发展至关重要。 Will Will Will Will Will Will Will Will Will在他的导师Carl June N Proteomics和宾夕法尼亚大学经验丰富的合作者的生物信息学和生物信息学中的一些分子生物学培训。攻击AML- d的特定免疫治疗剂将建立一个学术途径，以发现和开发新的嵌合抗原受体T细胞方法。