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)

• 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
• 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; 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

 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（由适用提供）：除了极少数例外，急性骨髓性白血病（AML）的治疗在过去40年中几乎没有改变，并且长期的总生存期的稳定稳定约为30％。由申请人心理学博士Carl June指导的小组被公认为是血液学恶性肿瘤的遗传学T细胞疗法领域的世界领导者，最近在治疗CD19+ B细胞白血病方面取得了广泛的成功。在某种程度上，这种疗法的成功取决于CD19的组织表达受限以及患者耐受正常B细胞​​长期部署的能力。与B细胞白血病相反，AML提出了一系列独特的挑战，因为它从根本上是造血干/祖细胞的癌症。因此，限制强大免疫疗法方法AML的采用的基本挑战是缺乏真正的白血病特异性抗原。这项研究的长期目标是将CAR-T细胞方法应用于AML。作为追求上述目标的下一步的总体目标是确定治疗AML的安全方法，而无需危害正常组织。中心假设是，单独或组合仔细选择目标特异性汽车构建体，可以最大化目标效率，同时最大程度地减少靶向脱靶毒性的后果。在强有力的初步数据的指导下，将通过追求三个特定目的来检验该假设：1）设计分配信号的汽车构建体的设计，其中激活是在遇到两种抗原的T细胞上的条件，从而增加了汽车刺激的特异性； 2）证明CAR-T细胞的髓质外肿瘤效应可以作为HCT的新型细胞调节方案来利用； 3）使用蛋白质组学随后进行生物信息学分析来鉴定AML中新型细胞表面靶标。申请人认为，这种方法是创新的，因为它偏离了现状 通过使用新颖的目标发现方法以及使用条件表达汽车构建体的现有AML目标的实用性来扩展可用AML目标的范围。拟议的研究很重要，因为它将贡献（临床反应）和广度（符合条件治疗的治疗疗法）的深度 反对AML。最终，这种知识有可能垂直推进AML和其他恶性肿瘤中通过嵌合抗原受体重新定向的T细胞免疫疗法的新兴领域。提出的研究活动对于申请人作为独立资助的身体科学家的发展至关重要，重点是细胞免疫疗法。吉尔博士将从他的心理Carl June获得进一步的分子生物学培训，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。因此，在培训期结束时，申请人将获得一套独特的智力和技术技能，这将使他能够攻击AML- 一次特定的免疫治疗剂一次从几个角度出发。此外，该奖项将支持转化研究中的独特培训经验，并将为新的嵌合抗原受体T细胞方法的发现和开发建立学术途径。