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

 描述（由申请人提供）：除了极少数例外，急性髓细胞白血病（AML）的治疗在过去40年中几乎没有变化，长期总生存率稳定在约30%。由申请人的导师Carl June博士领导的小组被公认为血液恶性肿瘤基因工程T细胞疗法领域的世界领导者，最近在治疗CD 19 + 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CD 19的有限组织表达和患者耐受正常B细胞长期耗竭的能力。与B细胞白血病相比，AML提出了一系列独特的挑战，因为它基本上是造血干细胞/祖细胞的癌症。因此，限制强大的免疫治疗方法应用于AML的潜在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，总体目标是确定治疗AML而不危及正常组织的安全方法。中心假设是，仔细选择靶向特异性CAR构建体（无论是单独还是组合）可以最大限度地提高靶向功效，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，将通过追求三个具体目标来测试该假设：1）设计分裂信号传导CAR构建体，其中活化是以T细胞遇到两种抗原为条件的，从而增加CAR刺激的特异性; 2）证明CAR-T细胞的清髓性脱瘤效应可以用作HCT的新型细胞调节方案;和3）使用蛋白质组学随后进行生物信息学分析鉴定AML中的新细胞表面靶标。申请人认为，这一方法是创新的，因为它不同于现状 通过使用新的靶向发现方法扩展可用AML靶标的范围，以及使用条件表达CAR构建体扩展现有AML靶标的效用。拟议的研究是重要的，因为它将有助于深度（临床反应）和广度（潜在的治愈性治疗的资格）的治疗武器库 针对AML。最终，这些知识有可能垂直推进AML和其他恶性肿瘤中嵌合抗原受体重定向T细胞免疫疗法的新兴领域。 拟议的研究活动对于申请人作为独立资助的医生-科学家的发展至关重要，重点是细胞免疫疗法。吉尔博士将从他的导师卡尔·琼博士那里接受分子生物学方面的进一步培训，并从宾夕法尼亚大学经验丰富的合作者那里接受蛋白质组学和生物信息学方面的培训。因此，在培训期结束时，申请人将获得一套独特的知识和技术技能，使他能够解决反洗钱问题， 从几个角度同时进行特异性免疫治疗。此外，该奖项将支持转化研究的独特培训经验，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。

 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.