Cytotoxic-T-Lymphocyte (CTL) Therapy of AML

AML 的细胞毒性 T 淋巴细胞 (CTL) 疗法

• 批准号: 8018627
• 负责人: Bruce R Blazar
• 金额: $ 28.92万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018627
• 关键词: Acute Myelocytic Leukemia; Address; Affect; Allogeneic Bone Marrow Transplantation; Animals; Apoptosis; Biological; Cell Death; Cells; Cessation of life; Coupled; Cytotoxic T-Lymphocytes; Data; Defect; Dioxygenases; Dominant-Negative Mutation; Environment; Enzymes; Generations; Goals; Health Benefit; Hematologic Neoplasms; Hematopoietic Neoplasms; Home environment; Homing; Imaging Techniques; Immune; Immune system; Immunotherapy; Interferon Type II; Kinetics; Knock-out; Life; Ligands; Limb structure; Location; Lymphocyte; Lymphocyte Function; Lymphocyte antigen; Malignant Neoplasms; Memory; Modeling; Mus; Patients; Phase; Process; Public Health; Regulation; Regulatory T-Lymphocyte; Residual Tumors; Role; Site; Solid Neoplasm; T-Lymphocyte; TNFSF10 gene; Technology; Testing; Transgenic Mice; Transgenic Organisms; Tryptophan; Tumor Necrosis Factor-alpha; base; cancer therapy; cell motility; clinically relevant; cytotoxic; exhaustion; in vivo; indoleamine; infectious disease treatment; insight; migration; novel; programs; response; tumor

Our goal is to develop strategies to treat acute myelogenous leukemia (AML) using immune-based therapies. We hypothesize that there is a fundamental defect in the efferent phase of anti-AML cytotoxicT lymphocyte (CTL) responses. To overcome this limitation, we first need to define the biological principles that limit the efferent limb of the immune system since no matter how effective we are in bolstering the afferent limb of CTL generation, a significant defect in the effector limb will limit efficacy. For effective and long- lasting anti-tumor responses, effector CTLs must be able to home to the appropriate locations, expand to reach a critical threshold for anti-tumor responses, survive the contraction phase, and retain persistant function as a memory cells to control residual disease. To test our hypotheses regarding the limits of these steps and how metastatic AML cells affect these processes, we will focus on efferent phase defects in CTL function using a model of ex vivo generated anti-AML CTLs that are transferred into tumor bearing mice with established AML. Thus, we will fill a critical gap in the field as to the endogenous mechanisms that create fundamental limitations of effector phase of CTL responses to hematological malignancy, and ultimately leading to clinically applicable strategies to overcome each of these defects. Aim 1: To define and overcome the extrinsic (host) mechanisms limiting the initial expansion of adoptively transferred anti-AML CTLs to sites of disseminated AML. We will test the hypothesis that host regulatory T cells and the intracellular enzyme indoleamine 2,3 dioxygenase (IDO) as endogenous suppressors of CTL expansion and function, uses unique knockout and transgenic strains using state of the art imaging techniques. Aim 2: To define and overcome the intrinsic CTL mechanisms limiting the expansion, persistence and function of anti-AML CTLs in mice with disseminated AML. We will define the role of activation induced cell death by interferon-gamma and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on anti-AML CTLs. We will define the role of negative regulation by cytotoxic lymphocyte antigen-4 (CTLA4) on transferred CTLs using a novel cell-intrinsic dominant-negative inhibition strategy to selectively block CTLA4 function only in the transferred CTLs. Lastly, we will define the role of negative regulatory molecule, programmed death-1 (PD-1), on CTL expansion and CTL "exhaustion. Public Health Benefits. Our goal is to develop clinically relevant approaches that will facilitate adoptive T cell immunotherapy to treat patients with cancer. The fundamental insights gained from these studies will have broad implications relevant to both cancer therapy and treatment of infectious diseases .

我们的目标是制定使用基于免疫的策略来治疗急性骨髓性白血病（AML） 疗法。我们假设在抗AML细胞毒素的传出阶段存在基本缺陷 淋巴细胞（CTL）反应。为了克服这一限制，我们首先需要定义生物学原理 限制免疫系统的传出肢体，因为无论我们在加入的效果如何 CTL生成的肢体，效应子肢的显着缺陷将限制功效。有效且长期 持久的抗肿瘤反应，效应子CTL必须能够回家适当的位置，扩展到 达到抗肿瘤反应的关键阈值，在收缩阶段生存并保持持久性 充当控制残留疾病的记忆细胞。测试我们关于这些限制的假设 步骤以及转移性AML细胞如何影响这些过程，我们将重点关注CTL中的传出相缺陷 使用离体生成的抗AML CTL的模型，该抗AML CTL被转移到带有肿瘤的小鼠中 已建立的AML。因此，我们将填补现场的关键空白 CTL对血液系统恶性肿瘤的效应阶段的基本局限性，最终 导致临床适用的策略来克服这些缺陷中的每一个。目标1：定义和克服 外部（主机）机制限制了采用转移的抗AML CTL的初始扩展到站点 传播的AML。我们将测试宿主调节性T细胞和细胞内酶的假设 吲哚胺2,3二氧酶（IDO）作为CTL扩展和功能的内源性抑制器 使用艺术成像技术的独特敲除和转基因菌株。目标2：定义和 克服限制抗AML CTL的膨胀，持久性和功能的内在CTL机制 在传播AML的小鼠中。我们将定义干扰素伽马激活诱导细胞死亡的作用 抗AML CTL上的与肿瘤坏死相关的凋亡诱导配体（TRAIL）。我们将定义 使用新颖的CTL对细胞毒性淋巴细胞抗原4（CTLA4）负调控的作用 仅在转移中，仅在转移中才能选择性地阻断CTLA4功能 CTL。最后，我们将定义负调节分子，程序性死亡-1（PD-1）在CTL上的作用 扩展和CTL“精疲力尽。 公共卫生益处。我们的目标是开发临床相关的方法，以促进收养T细胞 免疫疗法治疗癌症患者。从这些研究中获得的基本见解将具有 与癌症治疗和传染病的治疗相关的广泛含义。