MOLECULAR MANIPULATION TO ENHANCE ANTI-MYELOMA RESPONSE

分子调控增强抗骨髓瘤反应

• 批准号: 8332546
• 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/8332546
• 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; Caucasoid Race; Cell Survival; Cell physiology; Cells; Clinical; Clinical Protocols; Competence; Data; Development; Diagnosis; Disease; Effector Cell; Functional disorder; Funding; Gene Expression Profile; Gene Targeting; Genes; 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; 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; 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; peripheral blood; pre-clinical; public health relevance; 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）： 在我们先前利用骨髓瘤特异性抗原（白痴）和多发性骨髓瘤（MM）基于细胞的疫苗的研究中，我们观察到抗原特异性免疫响应的诱导；但是，没有看到临床反应。为了实现临床上有意义的免疫响应，在上一个资金期间，我们进一步研究了MM的免疫能力。我们评估了MM和单克隆肾上腺病患者的乙型肝炎疫苗免疫响应的发育（MGUS），并观察到MM的免疫功能在MM中显着受损，并且在MGUS患者中也受到了很大的损害。我们的进一步研究已经确定了影响骨髓瘤免疫稳态的功能失调的T调节细胞，以及影响骨髓瘤细胞生长和存活的上调TH17细胞，并抑制了Th1免疫血液。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）。已经出现了一大批信息，支持了骨髓（BM）微环境在不仅支持MM细胞生长和生存中的关键作用，而且在诱导的免疫功能障碍方面也支持。根据介体6（IL-6），转化生长因子-Beta（TGF- - ）和IL-1的信息，MM中升高，并且可能在T细胞功能中起重要作用，我们假设在BM微型环境中产生的条件通过MM细胞与MM细胞和骨骼莫尔斯型细胞（BMSC）的相互作用（BMSC）进行调节（BMSC）在MM中的相互作用（BMSC）中，以MMS（BMSC）进行MM，以MMS的调节，以促进MM和MG构成MM，以促进MM和MG构成MM的MM，以MM和MM构成MM的MM，以MM和MM构成MM的MM群体。这些条件可能使我们能够改善免疫调查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细胞在促进MM中免疫功能障碍和肿瘤生长中的失衡（特定目标1）。在这个目标中，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和分子确定剂，及其与MM和MGU中BM微环境中的Th17细胞的相互作用及其与Th17细胞的相互作用。我们将利用来自MGU的患者的配对样品，以了解骨髓瘤，以了解免疫剂量从MGUS进展到MM的变化。此外，我们将评估Treg和Th17细胞对MM细胞生长以及生存和免疫响应的促炎细胞因子的直接和间接作用。我们将研究免疫调查的调节剂，以克服在MM中观察到的免疫抑制作用，以增强效应子T细胞功能（特定目标2）。我们将表征MGU和MM患者的外周血和骨髓中的抗MM效应T细胞反应与正常个体相比，与MM相关的抗原XBP-1，OFD-1和SOX-2，然后评估了免疫功能的调节剂（抗IL-17，抗IL-17，Anti-il-6和Revlimid），单独使用Anti-il-6和Revimid和ROMPINCER COMBININCTION TO RENCOR t in CYROR t n效率。当我们定义MM中免疫压迫的介体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策略，并结合免疫功能调节剂。 （特定目标3）。我们已经分析了我们大型临床注释的基因表达谱，来自骨髓瘤患者的替代剪接和拷贝数改变数据，并鉴定出和验证了临床关键的基因。现在，我们将评估针对CTL反应的这些基因的免疫学相关肽。最后，我们将结合免疫调节剂和肽疫苗，以产生强大的免疫响应。拟议的研究将确定骨髓瘤中免疫抑制的机制，开发改善免疫功能的方法，并开发基于肽的疫苗策略，以便临床前临床应用。