Modulation of T cell Homeostasis in Myelodysplastic Syndrome (MDS)

骨髓增生异常综合征 (MDS) 中 T 细胞稳态的调节

• 批准号: 7534217
• 负责人: Pearlie K Burnette
• 金额: $ 28.8万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-18 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7534217
• 关键词: Acute Myelocytic Leukemia; Affect; Age; Aging; Animal Model; Antigen Presentation; Antigens; Autoimmune Process; Award; Binding; Biological Assay; Blood; Bone Marrow; CD28 gene; Cancer Patient; Cancer Vaccines; Cell physiology; Cells; Class; Clinical; Combined Modality Therapy; Data; Defect; Development; Disease; Dose; Dysmyelopoietic Syndromes; Etiology; Event; Gene Mutation; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Homeostasis; Immunity; Immunologics; Immunotherapy; In Vitro; Individual; Inflammatory; K-562; Laboratories; Life; Molecular; Parents; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phase; Phosphoric Monoester Hydrolases; Population; Population Dynamics; Protein Overexpression; Protein Phosphatase 2A Regulatory Subunit PR53; Protein Tyrosine Kinase; Public Health; Receptor Signaling; Recruitment Activity; Reporting; Repression; Research Design; Risk; Signal Transduction; Syndrome; T Cell Receptor Signaling Pathway; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TNFSF5 gene; Testing; Thalidomide; Therapeutic; Tumor Antigens; United States Food and Drug Administration; Vaccine Therapy; Vaccines; age related; anergy; cancer risk; cancer therapy; cytokine; cytopenia; genetic manipulation; human old age (65+); improved; in vivo; inhibitor/antagonist; interest; lenalidomide; leukemia; neoplastic; novel; prevent; receptor; response; tumor

DESCRIPTION (provided by applicant): Myelodysplastic syndromes (MDS) are characterized by incompetent hematopoiesis that leads to single or multi-lineage peripheral cytopenias with the development of acute myeloid leukemia (AML) in approximately 30-40% of cases. The etiology of MDS is unknown and the factors leading to AML progression are not well characterized. With similarity to other cancer patients, MDS patients have defects in proximal T-cell receptor signaling pathways and altered T-cell homeostasis. A new class of interesting therapeutic drugs (IMiDs), derived from the parent compound thalidomide, has shown activity in a variety of inflammatory, autoimmune, and neoplastic diseases including MDS where clinical responses were observed and the drug was awarded FDA approval in select patients. Lenalidomide, as well as other IMiDs, possess a unique ability to augment T-cell function by substituting for inadequate secondary antigen-independent co-stimulatory signals through an unknown mechanism that involves activation of the CD28 receptor. Lenalidomide was able to reverse peripheral T-cell anergy, enhance TH1-type cytokine responses, and change T-cell homeostasis in patients with MDS. Although treatments to activate T-cell signaling and expansion have been used, activation in general does not alter T-cell subset distribution or preferentially activate antigen-specific T-cells. Importantly, animal models of IMiDs combined with cancer vaccines suggest that these drugs selectively enhance anti-tumor specific T-cell responses. Therefore, we hypothesize that reversal of the T-cell signaling defects and improved T-cell homeostasis with lenalidomide along with a cellular vaccine that is cross-reactive to endogenous tumor antigens should result in an effective therapeutic treatment that will prevent leukemia progression in MDS. To examine the proposed hypothesis, we will perform three specific aims. In Aim 1, the molecular mechanism of lenalidomide-induced proximal T-cell receptor signaling events will be investigated in vitro. We found that lenalidomide acts as an inhibitor of PP2A phosphatase activity. PP2A is known to bind and possibly repress the YXXM PI3K binding motif in the CD28 receptor intracellular domain that recruits and/or activates proximal signaling intermediates at the level of the T-cell/CD28 pathway. To determine whether inhibition of PP2A repression in the YXXM region is responsible for the co-stimulatory function of lenalidomide, in vitro binding assays, protein tyrosine kinase activation assays, phosphatase function, genetic manipulation of signaling components in primary cells, and overexpression of the CD28 receptor carrying genetic mutations in the YXXM region will be performed. In Aim 2, studies are designed to identify the mechanisms responsible for changes in T-cell population dynamics in response to leukemia-associated antigens after MDS patients are treated in vivo with lenalidomide therapy. As an ultimate test of our hypothesis, we plan to perform a Phase I dose-escalation trial of the K562 "bystander" cellular vaccine that is transduced with the genes for GM-CSF and CD40L in combination with the FDA-approved dose of lenalidomide in high-risk MDS patients. The goal of Aim 3 is to determine whether this vaccine/lenalidomide therapy modulates antigen-specific T-cell response against endogenous leukemia-associated antigens present in the bone marrow of MDS patients. PUBLIC HEALTH RELEVANCE: Myelodysplastic syndromes (MDS) are characterized by defective blood formation and high risk for leukemia development and primarily occur in individuals over the age of 65 years old. New strategies of treatment are needed for age-related diseases such as MDS as the US population ages. For tumor vaccine therapies to produce clinical responses in MDS and in cancer patients, appropriate antigen selection, intact antigen presentation, and T-cell function are all critical. We propose a new combination therapy in which a novel cellular vaccine will be combined with a new drug to attack all aspects of this problem. We believe that this new treatment strategy is best tested in the setting of high-risk MDS that generally have poor survival, limited treatment options, and who may have a clinical response to the drug alone. Mechanistic studies will aide our understanding of T-cell immunity and improve our ability to utilize this form of immunotherapy and other forms for the treatment of cancer in general.

描述（由申请人提供）：骨髓增生综合征（MDS）的特征是无能的造血症，导致急性髓样白血病（AML）在大约30-40％的情况下导致单一或多部外周围细胞质细胞增多症。 MDS的病因尚不清楚，导致AML进展的因素没有很好地表征。 MDS患者与其他癌症患者相似，在T细胞受体信号通路和T细胞稳态改变方面存在缺陷。源自母体化合物沙利度胺的一类新的有趣的治疗药物（IMID）在各种炎症性，自身免疫性和肿瘤疾病中都表现出活性，包括观察到临床反应并在某些患者中授予FDA批准的MDS。 Lenalidomide以及其他IMID具有通过涉及CD28受体激活的未知机制来代替二次抗原独立的共刺激信号，具有唯一增强T细胞功能的能力。 Lenalidomide能够逆转外围T细胞厌食，增强Th1型细胞因子反应，并改变MDS患者的T细胞稳态。尽管已经使用了激活T细胞信号传导和膨胀的处理方法，但通常不会改变T细胞子集分布或优先激活抗原特异性T细胞。重要的是，与癌症疫苗相结合的动物模型表明，这些药物有选择地增强了抗肿瘤特异性T细胞反应。因此，我们假设T细胞信号传导缺陷的逆转和与周期性胺的T细胞稳态以及改善的T细胞稳态以及对内源性肿瘤抗原具有交叉反应的细胞疫苗应导致有效的治疗治疗，从而可以防止MDS中的白血病进展。为了审查提出的假设，我们将执行三个具体目标。在AIM 1中，将在体外研究Lenalidomide诱导的T细胞受体信号传导事件的分子机制。我们发现，Lenalidomide充当PP2A磷酸酶活性的抑制剂。已知PP2A结合并可能抑制CD28受体内细胞内结构域中的YXXM PI3K结合基序，该基元在T-Cell/CD28途径的水平上募集和/或激活近端信号传导中间体。为了确定YXXM区域中PP2A抑制的抑制是否负责列纳替胺的共刺激功能，体外结合测定，蛋白质酪氨酸激酶激活，磷酸酶的功能，遗传操作，遗传性操纵在原代细胞中信号成分的遗传操纵以及CD28受体的过度表达的cd28受体中的遗传性均具有Yxx in yxx的佳能。在AIM 2中，研究旨在识别导致T细胞种群动力学变化的机制，以响应于与Lenalidomide治疗的MDS患者在体内治疗MDS患者后与白血病相关的抗原。作为对我们假设的最终检验，我们计划对GM-CSF和CD40L基因转导的K562“旁观者”细胞疫苗进行I期剂量降低试验，并结合FDA批准的高风险MDS患者的Lenalidomase的FDA批准剂量。 AIM 3的目的是确定这种疫苗/列纳替麦治疗是否调节了MDS患者骨髓中存在的内源性白血病相关抗原的抗原特异性T细胞反应。公共卫生相关性：骨髓增生性综合征（MDS）的特征是血液形成缺陷和白血病发育的高风险，主要发生在65岁以上的个体中。对于年龄相关的疾病，例如美国人口年龄，需要新的治疗策略。为了使肿瘤疫苗疗法在MDS和癌症患者中产生临床反应，适当的抗原选择，完整的抗原表现和T细胞功能都是至关重要的。我们提出了一种新的联合疗法，其中新型的细胞疫苗将与一种新药结合使用，以攻击该问题的所有方面。我们认为，这种新的治疗策略最好在通常生存率较差，治疗选择有限的高风险MDS的情况下进行测试，并且仅对该药物有临床反应。机械研究将有助于我们对T细胞免疫的理解，并提高我们利用这种免疫疗法和其他形式的癌症治疗的能力。