MOLECULAR MANIPULATION TO ENHANCE ANTI-MYELOMA RESPONSE

分子调控增强抗骨髓瘤反应

• 批准号: 8963449
• 负责人: Nikhil C. Munshi
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963449
• 关键词: Affect; African American; Age; Alternative Splicing; Antigen Presentation; Antigens; B lymphoid malignancy; Blood Circulation; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; Caucasians; Cell Survival; Cell physiology; Cells; Clinical; Clinical Protocols; Competence; Data; Development; Diagnosis; Disease; Effector Cell; Functional disorder; Funding; Gene Expression Profile; Gene Targeting; Genes; Health; Hepatitis B Vaccination; High Dose Chemotherapy; Homeostasis; Immune; Immune System Diseases; Immune response; Immunoglobulin Idiotypes; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Incidence; Individual; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-17; Interleukin-6; Investigation; Lead; Mediator of activation protein; Medical center; Methods; Modality; Molecular; Molecular Abnormality; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Outcome; Patients; Peptides; Performance Status; Peripheral; Placebos; Play; Population; Prevalence; Production; Randomized; Records; Regulatory T-Lymphocyte; Revlimid; Risk; Role; Sampling; Schedule; Stromal Cells; T cell response; T-Lymphocyte; Therapeutic; Toxic effect; Transforming Growth Factor beta; Vaccination; Veterans; antitumor effect; base; cell growth; clinical application; cytokine; dosage; effective therapy; immune function; improved; in vivo; interleukin-22; interleukin-23; novel therapeutic intervention; older patient; patient population; peptide vaccination; peripheral blood; pre-clinical; response; tumor growth; tumor progression; vaccination strategy

DESCRIPTION (provided by applicant): In our prior studies utilizing myeloma specific antigen (idiotype) and multiple myeloma (MM) cell-based vaccination, we observed induction of antigen-specific immune responses; however, clinical responses were not seen. To achieve clinically meaningful immune response, in the previous funding period, we further investigated immune-competence in MM. We evaluated development of immune response to Hepatitis B vaccination in patients with MM and monoclonal gammopathy of undetermined significance (MGUS) and observed that immune function is significantly impaired in MM and interestingly also in patients with MGUS. Our further investigations have identified both dysfunctional T regulatory cells that affect immune homeostasis in myeloma, and up-regulated Th17 cells that affects both myeloma cell growth and survival as well as suppress Th1 immune responses. Moreover these cells produce cytokines (IL-17, IL-21, IL-22, IL-23 and IL- 27) with significant immunosuppressive activity. A significant body of information has emerged supporting a critical role for the bone marrow (BM) microenvironment in supporting not only MM cell growth, and survival, but also in inducing the immune dysfunction. Based on the information that interleukin-6 (IL-6), transforming growth factor-beta (TGF-¿), and IL-1 are elevated in MM and may play an important role in T cell function we hypothesize that conditions generated in BM microenvironment by interaction between MM cells and bone marrow stromal cells (BMSC) modulate the immune responses to support tumor progression in MGUS and in MM and targeting these conditions may allow us to improve immune responses and develop immunotherapeutic strategies. Towards this overall objective we will evaluate the role of regulatory T cells (Treg) and their imbalance with TH17 cells in the promotion of immune dysfunction and tumor growth in MM (Specific Aim 1). In this objective we will first investigate both qualitative and quantitative aberrations and molecular determinants of regulatory T cell dysfunction and its interplay with Th17 cells in the BM microenvironment and peripheral circulation in MM and MGUS. We will utilize paired samples from patients' with MGUS progressing to myeloma to understand the change in immune make up from MGUS progression to MM. Additionally, we will evaluate the direct and indirect effects of pro-inflammatory cytokines produced by Treg and Th17 cells on MM cell growth and survival and immune response. We will investigate modulators of immune responses to overcome immune suppressive effects observed in MM to augment effector T cell function (Specific Aim 2). We will characterize the anti-MM effector T cell responses in peripheral blood and bone marrows of MGUS and MM patients compared with normal individuals against MM-related antigens Xbp-1, OFD-1 and Sox-2 and then evaluate modulators of immune function (anti- IL-17, anti-IL-6 & Revlimid) alone and in combination to improve T effector cell-functions in MM. As we define the mediators of immune suppression in MM and investigate agents able to overcome the suppressive effects, we will develop antigen specific peptide-based vaccination strategy in combination with modulators of immune function. (Specific Aim 3). We have analyzed our large clinically annotated gene expression profile, alternate splicing and copy number alterations data from myeloma patients and identified and validated clinically critical genes. We will now evaluate immunologically relevant peptides targeting these genes for CTL response. Finally we will combine the immune modulators and peptide vaccination to generate robust immune response. The proposed studies will identify the mechanism of immune suppression in myeloma, develop methods to improve immune function and develop peptide-based vaccination strategies to preclinical rational for their clinical application.

描述（由申请人提供）： 在我们之前利用骨髓瘤特异性抗原（独特型）和多发性骨髓瘤（MM）细胞疫苗接种的研究中，我们观察到抗原特异性免疫反应的诱导；然而，没有看到临床反应。为了实现具有临床意义的免疫反应，在之前的资助期间，我们进一步研究了 MM 的免疫能力。我们评估了 MM 和意义未明的单克隆丙种球蛋白病 (MGUS) 患者对乙型肝炎疫苗接种的免疫反应的发展，并观察到 ​​MM 患者的免疫功能显着受损，有趣的是 MGUS 患者的免疫功能也显着受损。我们的进一步研究发现，功能失调的 T 调节细胞会影响骨髓瘤中的免疫稳态，上调的 Th17 细胞会影响骨髓瘤细胞的生长和存活并抑制 Th1 免疫反应。此外，这些细胞产生具有显着免疫抑制活性的细胞因子（IL-17、IL-21、IL-22、IL-23和IL-27）。大量信息表明骨髓 (BM) 微环境不仅在支持 MM 细胞生长和存活方面发挥着关键作用，而且在诱导免疫功能障碍方面也发挥着关键作用。基于白细胞介素-6 (IL-6)、转化生长因子-β (TGF-¿) 和 IL-1 在 MM 中升高并且可能在 T 细胞功能中发挥重要作用的信息，我们假设通过 MM 细胞和骨髓基质细胞 (BMSC) 之间的相互作用在 BM 微环境中产生的条件调节免疫反应，以支持 MGUS 和 MM 中的肿瘤进展，并针对这些条件 可能使我们能够改善免疫反应并制定免疫治疗策略。为了实现这一总体目标，我们将评估调节性 T 细胞 (Treg) 的作用及其与 TH17 细胞的不平衡在促进 MM 免疫功能障碍和肿瘤生长中的作用（具体目标 1）。在此目标中，我们将首先研究调节性 T 细胞功能障碍的定性和定量畸变以及分子决定因素及其与 BM 微环境和 MM 和 MGUS 外周循环中 Th17 细胞的相互作用。我们将利用 MGUS 进展为骨髓瘤患者的配对样本来了解从 MGUS 进展为 MM 期间免疫组成的变化。此外，我们将评估 Treg 和 Th17 细胞产生的促炎细胞因子对 MM 细胞生长、存活和免疫反应的直接和间接影响。我们将研究免疫反应调节剂，以克服在 MM 中观察到的免疫抑制效应，从而增强效应 T 细胞功能（具体目标 2）。我们将表征 MGUS 和 MM 患者的外周血和骨髓中与正常个体相比针对 MM 相关抗原 Xbp-1、OFD-1 和 Sox-2 的抗 MM 效应 T 细胞反应，然后评估单独和组合的免疫功能调节剂（抗 IL-17、抗 IL-6 和 Revlimid）以改善 MM 中的 T 效应细胞功能。当我们定义多发性骨髓瘤中免疫抑制的介质并研究能够克服抑制作用的药物时，我们将开发基于抗原特异性肽的疫苗接种策略，并与免疫功能调节剂相结合。 （具体目标 3）。我们分析了来自骨髓瘤患者的大量临床注释基因表达谱、可变剪接和拷贝数改变数据，并鉴定和验证了临床关键基因。我们现在将评估针对这些基因的 CTL 反应的免疫相关肽。最后，我们将结合免疫调节剂和肽疫苗接种以产生强大的免疫反应。拟议的研究将确定骨髓瘤免疫抑制的机制，开发改善免疫功能的方法，并开发基于肽的疫苗接种策略，以使其临床应用合理。