Cytotoxic-T-Lymphocyte (CTL) Therapy of AML

AML 的细胞毒性 T 淋巴细胞 (CTL) 疗法

• 批准号: 7265838
• 负责人: Bruce R Blazar
• 金额: $ 29.82万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7265838
• 关键词: Acute; Acute Myelocytic Leukemia; Address; Affect; Allogeneic Bone Marrow Transplantation; Animals; Apoptosis; Arts; 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; Localized; Location; Lymphocyte Function; Lymphocyte antigen; Malignant Neoplasms; Memory; Modeling; Mus; Myeloid Leukemia; Patients; Phase; Process; Public Health; Regulation; Residual Tumors; Role; Site; Solid Neoplasm; T-Lymphocyte; Technology; Testing; Transgenic Organisms; Tryptophan; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; base; cancer therapy; cell motility; clinically relevant; cytotoxic; exhaustion; human TNF protein; in vivo; indoleamine; infectious disease treatment; insight; migration; novel; programs; response; tumor

DESCRIPTION (provided by applicant): 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 cytotoxic T 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.

描述（由申请人提供）：我们的目标是开发使用基于免疫的疗法治疗急性髓性白血病（AML）的策略。我们推测，有一个基本的缺陷，在传出阶段的抗AML细胞毒性T淋巴细胞（CTL）反应。为了克服这一限制，我们首先需要定义限制免疫系统传出肢的生物学原理，因为无论我们在支持CTL产生的传入肢方面多么有效，效应肢中的显著缺陷都会限制功效。对于有效和持久的抗肿瘤应答，效应CTL必须能够归巢到适当的位置，扩增以达到抗肿瘤应答的临界阈值，在收缩期存活，并保持作为记忆细胞的持续功能以控制残留疾病。为了测试我们关于这些步骤的限制以及转移性AML细胞如何影响这些过程的假设，我们将使用离体产生的抗AML CTL的模型关注CTL功能的传出相缺陷，所述抗AML CTL被转移到具有已建立的AML的荷瘤小鼠中。因此，我们将填补一个关键的差距，在该领域的内源性机制，创造了根本的限制效应阶段的CTL反应血液恶性肿瘤，并最终导致临床上适用的策略，以克服这些缺陷。目标1：确定并克服限制过继转移抗AML CTL初始扩增至播散性AML部位的外在（宿主）机制。我们将测试宿主调节性T细胞和细胞内酶吲哚胺2，3双加氧酶（IDO）作为CTL扩增和功能的内源性抑制因子的假设，使用独特的敲除和转基因菌株，使用最先进的成像技术。目标二：确定并克服限制抗AML CTL在播散性AML小鼠中扩增、持续存在和功能的内在CTL机制。我们将确定γ-干扰素和肿瘤坏死因子相关凋亡诱导配体（TRAIL）对抗AML CTL的激活诱导细胞死亡的作用。我们将使用一种新的细胞内在显性负抑制策略来选择性地阻断仅在转移的CTL中的CTLA 4功能，来定义细胞毒性淋巴细胞抗原-4（CTLA 4）对转移的CTL的负调节作用。最后，我们将明确负调控分子程序性死亡-1（PD-1）在CTL扩增和CTL耗竭中的作用。 公共卫生福利：我们的目标是开发临床相关的方法，促进过继性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对癌症治疗和传染病治疗产生广泛的影响。