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: 7835533
• 负责人: Pearlie K Burnette
• 金额: $ 68.64万
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7835533
• 关键词: Acute Myelocytic Leukemia; Age; Animal Model; Antigen Presentation; Antigens; Biomedical Research; Blood; Bone Marrow; CD28 gene; CD3 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Cancer Vaccines; Cell Death; Cell physiology; Cells; Clinical; Clinical Trials; Complex; Contracts; Correlative Study; Data; Defect; Dependency; Development; Disease; Dysmyelopoietic Syndromes; Elderly; Engraftment; Erythroid; Evaluation; Flow Cytometry; Funding; Future; Generations; Goals; Grant; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Homeostasis; Hour; Human; Human Resources; Immunity; Immunodeficient Mouse; Immunosuppressive Agents; Immunotherapy; In Vitro; Individual; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Mus; Myelogenous; Natural Killer Cells; Pancytopenia; Parents; Patient Care; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacologic Substance; Phase I Clinical Trials; Phase II Clinical Trials; Phosphoric Monoester Hydrolases; Pilot Projects; Play; Population; Premalignant; Production; Progress Reports; Protein Phosphatase 2A Regulatory Subunit PR53; Rare Diseases; Receptor Signaling; Recovery; Regulation; Research; Resources; Risk; Role; Sampling; Science; Signal Transduction; T Cell Receptor Signaling Pathway; T memory cell; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Thalidomide; Therapeutic; Thymocyte Development; Thymus Gland; Time; Tissues; Transplantation; Tumor Antigens; United States National Institutes of Health; Vaccine Therapy; Vaccines; Work; Xenograft Model; Xenograft procedure; age related; base; cancer therapy; cost; cytokine; cytopenia; cytotoxic; cytotoxicity; drug discovery; high risk; human disease; human old age (65+); human tissue; immune function; improved; in vivo; indexing; innovation; lenalidomide; leukemia; meetings; mouse model; novel; parent grant; parent project; peripheral blood; prevent; public health relevance; receptor; reconstitution; research study; response; skills; therapeutic vaccine; treatment response; treatment strategy

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. With similarity to other cancer patients, MDS patients have defects in proximal T-cell receptor signaling pathways and altered T-cell homeostasis induced possibly by advanced age and a cancer-associated immunosuppressive microenvironment. A new class of therapeutic drugs (IMiDs), derived from the parent compound thalidomide 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. These results gave rise the hypothesis that reversal of the T-cell signaling defects and improved T-cell homeostasis with lenalidomide along with a cellular vaccine will prevent leukemia progression in MDS. Since initiating the grant, we have conclusively shown that lenalidomide suppresses the phosphatase PP2A. Importantly, we demonstrate that lenalidomide is associated with an age- dependent increase in naove CD4+ T cells that is associated with the pro-T cell response after lenaldiomide treatment. Given the age dependency, these results suggest that lenalidomide stimulates CD4+ naove cell release from the thymus and thus blocks a target that is involved in thymocyte development. The goal is to decipher the complex molecular mechanism of lenalidomide during T cell development and confirm that the drug improves vaccine responses in vivo. However, there are obvious limitations since the necessary experiments must be performed in vivo. To overcome this problem, we now propose supplemental experiments using a "humanized" mouse model created by engraftment of human tissues including hematopoietic stem cells (HSCs) and/or T cells into immunodeficient mice (Prkdcscid IL2r3-/- (NOD/Shi-scid IL2r-/- or NOG). To extend our studies on lenalidomide and cancer vaccines, we propose three new supplemental aims using this mouse model, 1) to determine if thymic function is necessary for naove production and lenalidomide-induced function in CD4+ T cells, 2) to determine if PP2A alters the molecular checkpoint for naove T cell generation and 3) to determine if vaccine administration in combination with lenalidomide modulates antigen-specific T-cell response against foreign and tumor-associated antigens in a xenograft transplantation model of high-risk MDS. The supplemental aims are highly novel and innovative with tremendous implications for the future advancement of science. This application meets the definitions and goals of the NIH recovery act for competitive revisions since the revised application fits the overall scope of the parent project (i.e., development of a therapeutic vaccine in MDS), the project will provide rigorous evaluation for a novel treatment to be applied to a specific human disease (i.e., MDS), the work proposed can be accomplished within a two-year period, the work will generate a novel resource (i.e., xenograft model applicable for future drug discovery efforts in MDS), increases hours for part-time staff, enables the hiring of new staff, retains current personnel, and contracts new key personnel with important skills necessary to complete these new aims. 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 humanized mouse model in which to study specific questions generated from preliminary data in the parent grant application to decipher the combined effects of lenalidomide and cellular vaccines. 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. The supplemental work fits the overall scope of the parent project (i.e., development of a therapeutic vaccine in MDS), the project will provide rigorous evaluation for a novel treatment to be applied to a specific human disease (i.e., MDS), the work proposed can be accomplished within a two-year period, the work will generate a novel resource (i.e., xenograft model applicable for future drug discovery efforts in MDS), increases hours for part-time staff, enables the hiring of new staff, retains current personnel, and contracts new key personnel with important skills necessary to complete these new aims.

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，约30-40%的病例发生急性髓性白血病（AML）。与其他癌症患者相似，MDS患者在近端T细胞受体信号传导途径中存在缺陷，并且可能由高龄和癌症相关免疫抑制微环境诱导T细胞稳态改变。衍生自母体化合物沙利度胺的一类新的治疗药物（IMiD）具有通过涉及CD 28受体活化的未知机制取代不充分的二级抗原非依赖性共刺激信号来增强T细胞功能的独特能力。这些结果提出了这样的假设：来那度胺沿着细胞疫苗逆转T细胞信号传导缺陷并改善T细胞稳态将预防MDS的白血病进展。自从启动资助以来，我们已经最终证明来那度胺抑制磷酸酶PP 2A。重要的是，我们证明来那度胺与新生CD 4 + T细胞的年龄依赖性增加相关，而新生CD 4 + T细胞与来那度胺治疗后的pro-T细胞应答相关。考虑到年龄依赖性，这些结果表明来那度胺刺激CD 4+细胞从胸腺释放，从而阻断参与胸腺细胞发育的靶点。目标是破译来那度胺在T细胞发育过程中的复杂分子机制，并证实该药物可改善体内疫苗反应。然而，由于必须在体内进行必要的实验，因此存在明显的局限性。为了克服这个问题，我们现在提出使用“人源化”小鼠模型的补充实验，所述小鼠模型通过将包括造血干细胞（HSC）和/或T细胞的人组织植入免疫缺陷小鼠（Prkdcscid IL 2 r 3-/-（NOD/Shi-scid IL 2 r-/-或NOG））中而产生。为了扩展我们对来那度胺和癌症疫苗的研究，我们使用该小鼠模型提出了三个新的补充目的，1）确定胸腺功能是否是CD 4 + T细胞中nove产生和来那度胺诱导的功能所必需的，2）确定PP 2A是否改变初始T细胞生成的分子检查点，和3）确定疫苗与来那度胺联合施用是否调节抗原特异性T细胞生成。在高危MDS异种移植模型中对外来抗原和肿瘤相关抗原的细胞应答。补充目标是非常新颖和创新的，对未来科学的进步有着巨大的影响。由于修订后的应用程序符合父项目的总体范围（即，MDS治疗性疫苗的开发），该项目将为应用于特定人类疾病的新治疗提供严格的评估（即，MDS），拟议的工作可以在两年内完成，这项工作将产生一种新的资源（即，新的研究计划包括：（a）增加非全职工作人员的工作时间，允许雇用新的工作人员，保留现有人员，并与具有完成这些新目标所需的重要技能的新的关键人员签订合同。 公共卫生关系：骨髓增生异常综合征（MDS）的特征在于有缺陷的血液形成和白血病发展的高风险，并且主要发生在65岁以上的个体中。随着美国人口老龄化，需要新的治疗策略来治疗年龄相关疾病，如MDS。对于在MDS和癌症患者中产生临床应答的肿瘤疫苗疗法，适当的抗原选择、完整的抗原呈递和T细胞功能都是至关重要的。我们提出了一种新的人源化小鼠模型，在该模型中研究从父母资助申请中的初步数据产生的特定问题，以破译来那度胺和细胞疫苗的联合作用。我们认为，这种新的治疗策略最好在高危MDS患者中进行测试，这些患者通常生存率低，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理解T细胞免疫，并提高我们利用这种形式的免疫疗法和其他形式治疗癌症的能力。补充工作符合父项目的总体范围（即，MDS治疗性疫苗的开发），该项目将为应用于特定人类疾病的新治疗提供严格的评估（即，MDS），拟议的工作可以在两年内完成，这项工作将产生一种新的资源（即，新的研究计划包括：（a）增加非全职工作人员的工作时间，允许雇用新的工作人员，保留现有人员，并与具有完成这些新目标所需的重要技能的新的关键人员签订合同。