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.

尽管对黑色素瘤的生物学、遗传学和免疫学的了解取得了进展，但晚期疾病患者的治疗结果仍然不佳。最近，在接受抗 CTLA4 抗体治疗的黑色素瘤患者中观察到总体生存率有所改善，这为更好的治疗迈出了一步。然而，进一步增强这种治疗功效的尝试仍然面临着多种在黑色素瘤携带者中发挥作用的免疫抑制因素。其中，备受关注的一个是黑色素瘤诱导 T 细胞耐受的能力。迄今为止，我们对 T 细胞无反应的表观遗传调控的研究表明，组蛋白脱乙酰酶抑制剂 (HDI) 具有影响黑色素瘤免疫原性和增强 T 细胞功能的双重能力，是一种有前景的免疫调节化合物。这些观察结果与我们的额外发现（HDAC6 和 HDAC11 分别调节黑色素瘤免疫原性和 T 细胞反应性）一起，为机械地解决 HDAC 在黑色素瘤免疫生物学中的作用提供了理论基础。因此，要测试的假设是特定 HDAC 的表观遗传操作是否可能增强黑色素瘤细胞的免疫原性和/或增强 T 细胞反应，从而导致免疫耐受的破坏和 CTLA4 阻断功效的增强。我们掌握的动物模型、分子和药理学工具以及（通过该 SPORE 的病理学核心）人类黑色素瘤样本将使我们能够深入了解 HDAC6 在黑色素瘤增殖、存活和免疫原性中的作用（目标 1）），以及 HDAC11 在 T 细胞抗黑色素瘤免疫中的作用（目标 2）。此外，临床核心提供的专业知识将有助于成功完成 I 期临床试验，该试验旨在评估 HDAC 抑制与抗 CTLA4 抗体联合治疗 IV 期黑色素瘤患者的安全性和免疫学效果（目标 3）。该团队努力产生的新知识将带来新型的基于表观遗传学的免疫疗法，通过克服黑色素瘤诱导的 T 细胞耐受的显着障碍，将提高 CTLA4 阻断的功效。