Cytotoxic-T-Lymphocyte (CTL) Therapy of AML

AML 的细胞毒性 T 淋巴细胞 (CTL) 疗法

• 批准号: 7554127
• 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/7554127
• 关键词: 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; Location; Lymphocyte; Lymphocyte Function; Lymphocyte antigen; Malignant Neoplasms; Memory; Modeling; Mus; 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; 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 .

我们的目标是开发策略，使用免疫为基础的治疗急性髓细胞白血病（AML） 治疗我们假设在抗AML细胞毒性T细胞的传出相存在根本性缺陷。 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分支，因为无论我们如何有效地支持传入分支， 在CTL产生的效应肢中，效应肢中的显著缺陷将限制功效。有效和长期- 为了获得持久的抗肿瘤应答，效应CTL必须能够归巢到适当的位置，扩展到 达到抗肿瘤反应的临界阈值，在收缩期存活，并保持持续性 作为记忆细胞来控制残留疾病。为了验证我们的假设， 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的传出相缺陷。 使用离体产生的抗AML CTL的模型，将其转移到荷瘤小鼠中， 建立AML。因此，我们将填补该领域的一个关键空白，即创造 对血液恶性肿瘤的CTL应答的效应期的基本局限性， 从而导致临床上可应用的策略来克服这些缺陷中的每一个。目标1：定义和克服 限制过继转移抗AML CTL初始扩增至位点的外在（宿主）机制 急性髓细胞白血病我们将检验宿主调节性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剂的用途 独特的基因敲除和转基因菌株，使用最先进的成像技术。目标2：定义和 克服限制抗AML CTL的扩增、持久性和功能的固有CTL机制 在患有播散性AML的小鼠中。我们将定义γ-干扰素激活诱导细胞死亡的作用 和肿瘤坏死因子相关凋亡诱导配体（TRAIL）。我们将定义 细胞毒性淋巴细胞抗原-4（CTLA-4）对转移的CTL的负调节作用 细胞内源性显性负抑制策略，仅在转移的细胞中选择性地阻断CTLA 4功能。 CTL。最后，我们将明确负调控分子程序性死亡-1（PD-1）在CTL中的作用 扩展和CTL“耗尽。 公共卫生福利。我们的目标是开发临床相关的方法，将促进过继性T细胞 免疫疗法来治疗癌症患者。从这些研究中获得的基本见解将 与癌症治疗和传染病治疗相关的广泛意义。