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

 描述(申请人提供)：除极少数例外，急性髓系白血病(AML)的治疗在过去40年中几乎没有变化，长期总存活率保持稳定在约30%。该小组由申请者的导师卡尔·琼博士领导，被公认为血液系统恶性肿瘤基因工程T细胞疗法领域的世界领导者，最近在治疗CD19+B细胞白血病方面取得了广泛的成功。在一定程度上，这种疗法的成功取决于CD19的组织表达受到限制，以及患者对正常B细胞长期耗竭的耐受能力。与B细胞白血病相比，AML提出了一系列独特的挑战，因为它从根本上是一种造血干细胞/祖细胞癌症。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，总体目标是确定在不危及正常组织的情况下治疗AML的安全方法。中心假设是，仔细选择靶标特定的CAR结构，无论是单独的还是组合的，都可以最大化靶标上的效果，同时将靶外毒性的后果降至最低。在强大的初步数据的指导下，这一假说将通过追求三个具体目标来检验：1)设计分裂信号CAR结构，其中激活是以T细胞遇到两个抗原为条件的，从而增加CAR刺激的特异性；2)证明CAR-T细胞的清髓性非肿瘤效应可被用作治疗HCT的新的细胞调节方案；以及3)使用蛋白质组学和生物信息学分析来鉴定AML中的新的细胞表面靶点。申请人认为，这种方法是创新的，因为它不同于现状 通过使用新的目标发现方法来扩展可用AML目标的范围，以及使用条件表达CAR构造来扩展现有AML目标的效用。这项拟议的研究意义重大，因为它将为治疗武器库贡献深度(临床反应)和广度(有资格接受潜在的根治疗法)。 对抗急性髓系白血病。最终，这些知识有可能在AML和其他恶性肿瘤中垂直推进嵌合抗原受体重定向T细胞免疫治疗这一新兴领域。拟议的研究活动对申请者成为一名独立资助的内科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·琼博士那里接受进一步的分子生物学培训，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，在培训结束时，申请者将获得一套独特的智力和技术技能，使他能够解决急性髓细胞白血病的问题- 同时从多个角度进行特异性免疫治疗。此外，该奖项将支持在翻译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细胞方法建立一条学术道路。

 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.