Augmenting the Immunogenicity of Melanoma Through Manipulation of Histone Deacet

通过组蛋白 Deacet 的操作增强黑色素瘤的免疫原性

基本信息

批准号：
8556443
负责人：
EDUARDO M. SOTOMAYOR
金额：
$ 27.64万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8556443
关键词：
Address Animal Model Antibodies Antigen-Presenting Cells Antigens Apoptosis Attention Biology CD4 Positive T Lymphocytes CD8B1 gene CTLA4 gene Cell Cycle Arrest Cell Proliferation Cell physiology Cells Clinical Collaborations Disease Epigenetic Process Face Genetic HDAC6 gene Hand Histone Deacetylase Histone Deacetylase Inhibitor Histones Human Immune Immune Tolerance Immune response Immunity Immunobiology Immunologics Immunology Immunosuppressive Agents Immunotherapeutic agent Immunotherapy In Vitro Innovative Therapy Interferons Interleukin-10 Knowledge Laboratories Lead Malignant Neoplasms Melanoma Cell Metastatic Melanoma Molecular Mus Outcome Pathology Pathway interactions Patients Phase I Clinical Trials Production Property Resistance Role STAT3 gene Safety Sampling Signal Transduction Skin Cancer Staging T cell regulation T cell response T-Lymphocyte Testing Toxic effect Treatment Efficacy base clinical effect clinically significant combinatorial cytokine frontier immunogenic immunogenicity immunoregulation improved in vivo inhibitor/antagonist insight melanoma neoplastic cell novel novel therapeutic intervention phase 1 study response tool tumor tumor immunology

项目摘要

In spite of the progress made in the understanding of the biology, genetics and immunology of melanoma, the outcome for patients with advanced-stage disease has remained poor. A step forward toward better therapies was recently provided by the improvement in overall survival observed in melanoma patients treated with an anti-CTLA4 antibody. Attempts to further augment the efficacy of this treatment would still face however a variety of immunosuppressive factors operative in melanoma-bearing hosts. Among those, one that has gained much attention is the ability of melanoma tumors to induce T-cell tolerance. Our studies to date of the epigenetic regulation of T-cell unresponsiveness point to histone deacetylase inhibitors (HDI) as promising immunomodulatory compounds given their dual ability to influence the immunogenicity of melanoma tumors and enhance T-cell function. These observations together with our additional findings that HDAC6 and HDAC11 regulates melanoma immunogenicity and T-cell responsiveness respectively, provided the rationale to mechanistically address the role of HDACs in melanoma immunobiology. The hypothesis to be tested is therefore whether epigenetic manipulation of specific HDACs might augment the immunogenicity of melanoma cells and/or augment T-cell responses leading to breaking of immune tolerance and enhancement of the efficacy of CTLA4 blockade. The animal models, molecular and pharmacological tools we have in hands together with the access (through the Pathology Core of this SPORE) to human melanoma samples would allow us to gain insights into the role of HDAC6 in melanoma proliferation, survival and immunogenicity (Aim 1), and the role of HDAC11 in T-cell anti-melanoma immunity (Aim 2). In addition, the expertise provided by the Clinical Core will allow the successful completion of a Phase I clinical trial aimed to assess the safety and immunologic effects of HDAC inhibition in combination with an anti-CTLA4 antibody in patients with stage IV melanoma (Aim 3). The new knowledge to be generated by this team effort would lead to novel epigenetic-based immunotherapy that by overcoming the remarkable barrier of melanoma-induced T-cell tolerance would improve the efficacy of CTLA4 blockade.

尽管在理解黑色素瘤的生物学，遗传学和免疫学方面取得了进展，但患有晚期疾病患者的结果仍然很差。最近，在用抗CTLA4抗体治疗的黑色素瘤患者中观察到的总体存活率的提高最近迈出了更好的疗法。试图进一步提高这种治疗的疗效仍将面临多种含有黑色素瘤宿主的免疫抑制因素。其中，引起了很多关注的是黑色素瘤诱导T细胞耐受性的能力。我们的研究迄今为止T细胞无反应性的表观遗传调节表明组蛋白脱乙酰基酶抑制剂（HDI）是有希望的免疫调节化合物，因为它们的双重能力影响了黑色素瘤肿瘤的免疫原性并增强T细胞功能。这些观察结果以及我们的其他发现，即HDAC6和HDAC11分别调节黑色素瘤的免疫原性和T细胞反应性，提供了机理上解决HDAC在黑色素瘤免疫生物学中的作用的基本原理。因此，要检验的假设是对特定HDAC的表观遗传操作是否可以增加黑色素瘤细胞的免疫原性和/或增强T细胞反应，从而导致免疫耐受性破坏并增强CTLA4封锁的功效。我们将动物模型，分子和药理学工具与进入人黑色素瘤样品的通道（通过该孢子的病理核心）共同拥有，这将使我们能够深入了解HDAC6在黑色素瘤增殖，生存和免疫原性中的作用（AIM 1）（AIM 1），以及HDAC11在T-Cell抗抗抗甲虫瘤中的作用（AIM 1）。此外，临床核心提供的专业知识将允许成功完成I期临床试验，旨在评估HDAC抑制与IV期黑色素瘤患者中抗CTLA4抗体结合使用的安全性和免疫学作用（AIM 3）。这项团队努力产生的新知识将导致新型的基于表观遗传的免疫疗法，通过克服黑色素瘤引起的T细胞耐受性的显着障碍将提高CTLA4阻断的功效。