Cytotoxic-T-Lymphocyte (CTL) Therapy of AML

AML 的细胞毒性 T 淋巴细胞 (CTL) 疗法

• 批准号: 7391632
• 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/7391632
• 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; 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

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 .

我们的目标是开发基于免疫的治疗急性髓性白血病（AML）的策略