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)： 在我们以前利用骨髓瘤特异性抗原(独特型)和多发性骨髓瘤(MM)细胞接种的研究中，我们观察到了抗原特异性免疫反应的诱导；然而，临床反应没有看到。为了达到临床上有意义的免疫反应，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患者和未确定意义的单克隆性伽马病(MGUS)患者接种乙肝疫苗后免疫反应的发展，观察到MM患者的免疫功能显著受损，有趣的是，MGUS患者的免疫功能也明显受损。我们进一步的研究发现，影响骨髓瘤免疫稳态的功能失调的T调节细胞，以及上调的Th17细胞，都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著免疫抑制活性的细胞因子(IL-17、IL-21、IL-22、IL-23和IL-27)。大量的信息支持骨髓(BM)微环境不仅在支持MM细胞的生长和存活方面起着关键作用，而且在诱导免疫功能障碍方面也起着关键作用。根据IL-6、转化生长因子-β和IL-1在MM中升高并可能在T细胞功能中发挥重要作用的信息，我们假设骨髓微环境中MM细胞和骨髓基质细胞(BMSC)相互作用产生的条件调节免疫反应以支持MGUS和MM中的肿瘤进展，针对这些条件可以使我们改善免疫反应并开发免疫治疗策略。朝着这个总体目标，我们将评估调节性T细胞(Treg)及其与TH17细胞的失衡在促进MM免疫功能障碍和肿瘤生长中的作用(特定目标1)。在这个目标中，我们将首先研究MM和MGUS骨髓微环境和外周循环中调节性T细胞功能障碍的定性和定量异常和分子决定因素及其与Th17细胞的相互作用。我们将利用从MGUS进展到骨髓瘤的患者的配对样本来了解从MGUS进展到MM的免疫构成的变化。此外，我们还将评估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的调节剂，以克服在多发性骨髓瘤中观察到的免疫抑制效应，以增强效应器T细胞功能(特定目标2)。我们将比较MGUS和MM患者外周血和骨髓中针对MM相关抗原XBP-1、OFD-1和SOX-2的抗MM效应T细胞反应的特征，然后评估单独和联合使用免疫功能调节剂(抗IL-17、抗IL-6和Revlimid)来改善MM的T效应细胞功能。(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、交替剪接和拷贝数改变数据，并识别和验证了临床关键基因。我们现在将评估针对这些基因的免疫相关多肽的CTL反应。最后，我们将结合免疫调节剂和多肽疫苗，以产生强大的免疫反应。这些研究将确定骨髓瘤的免疫抑制机制，开发提高免疫功能的方法，并开发基于多肽的疫苗策略，为其临床应用提供理论依据。