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: 8121398
• 负责人: Pearlie K Burnette
• 金额: $ 28.35万
• 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/8121398
• 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; Clinical; Combined Modality Therapy; Data; Defect; Development; Disease; Dose; Dysmyelopoietic Syndromes; Etiology; Event; FDA approved; Gene Mutation; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Health; 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 Phosphatase 2A Regulatory Subunit PR53; Protein Tyrosine Kinase; Receptor Signaling; Recruitment Activity; Reporting; Repression; Research Design; Signal Transduction; Syndrome; T Cell Receptor Signaling Pathway; T cell anergy; T cell response; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; TNFSF5 gene; Testing; Thalidomide; Therapeutic; Tumor Antigens; Vaccine Therapy; Vaccines; age related; cancer risk; cancer therapy; cytokine; cytopenia; genetic manipulation; high risk; human old age (65+); improved; in vivo; inhibitor/antagonist; interest; lenalidomide; leukemia; neoplastic; novel; overexpression; prevent; receptor; response; treatment strategy; 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）：骨髓增生异常综合征 (MDS) 的特征是造血功能不全，导致单系或多系外周血细胞减少，并在大约 30-40% 的病例中发展为急性髓性白血病 (AML)。 MDS 的病因尚不清楚，导致 AML 进展的因素尚不清楚。与其他癌症患者相似，MDS 患者存在近端 T 细胞受体信号通路缺陷和 T 细胞稳态改变。一类新型有趣的治疗药物 (IMiD) 源自母体化合物沙利度胺，已显示出对多种炎症、自身免疫和肿瘤疾病（包括 MDS）的活性，观察到了临床反应，该药物在选定的患者中获得了 FDA 批准。来那度胺以及其他 IMiD 具有增强 T 细胞功能的独特能力，通过涉及 CD28 受体激活的未知机制替代不充分的次级抗原非依赖性共刺激信号。来那度胺能够逆转 MDS 患者的外周 T 细胞无能性、增强 TH1 型细胞因子反应并改变 T 细胞稳态。尽管已使用激活 T 细胞信号传导和扩增的治疗方法，但激活通常不会改变 T 细胞亚群分布或优先激活抗原特异性 T 细胞。重要的是，IMiD 与癌症疫苗结合的动物模型表明这些药物选择性增强抗肿瘤特异性 T 细胞反应。因此，我们假设，使用来那度胺以及与内源性肿瘤抗原发生交叉反应的细胞疫苗来逆转 T 细胞信号传导缺陷并改善 T 细胞稳态，应该会产生有效的治疗方法，从而预防 MDS 中的白血病进展。为了检验所提出的假设，我们将实现三个具体目标。在目标 1 中，将在体外研究来那度胺诱导的近端 T 细胞受体信号传导事件的分子机制。我们发现来那度胺可作为 PP2A 磷酸酶活性的抑制剂。已知 PP2A 可以结合并可能抑制 CD28 受体胞内结构域中的 YXXM PI3K 结合基序，该结构域在 T 细胞/CD28 通路水平上募集和/或激活近端信号传导中间体。为了确定 YXXM 区域中 PP2A 抑制的抑制是否与来那度胺的共刺激功能有关，进行了体外结合测定、蛋白酪氨酸激酶激活测定、磷酸酶功能、原代细胞中信号成分的遗传操作以及 CD28 的过度表达将进行YXXM区域携带基因突变的受体。在目标 2 中，研究旨在确定 MDS 患者接受来那度胺体内治疗后，T 细胞群动态变化的机制，以响应白血病相关抗原。作为对我们假设的最终检验，我们计划对 K562“旁观者”细胞疫苗进行 I 期剂量递增试验，该疫苗是用 GM-CSF 和 CD40L 基因转导的，与 FDA 批准的来那度胺剂量相结合。高危MDS患者。目标 3 的目标是确定这种疫苗/来那度胺疗法是否可以调节针对 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：骨髓增生异常综合征 (MDS) 的特点是血液形成缺陷和罹患白血病的高风险，主要发生在 65 岁以上的个体中。随着美国人口老龄化，MDS 等与年龄相关的疾病需要新的治疗策略。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、完整的抗原呈递和 T 细胞功能都至关重要。我们提出了一种新的联合疗法，其中将新型细胞疫苗与新药物相结合，以解决该问题的各个方面。我们认为，这种新的治疗策略最好在高危 MDS 的环境中进行测试，这些患者通常生存率较差，治疗选择有限，并且可能对单独的药物有临床反应。机制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形式的免疫疗法和其他形式治疗一般癌症的能力。