Role of Immune Regulatory Pathways in BRAF targeted therapy In melanoma

免疫调节通路在黑色素瘤 BRAF 靶向治疗中的作用

• 批准号: 8744890
• 负责人: KEITH T FLAHERTY
• 金额: $ 28.81万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8744890
• 关键词: Autoimmunity; BRAF gene; Bone Marrow; Cells; Chimera organism; Clinical; Development; Disease remission; Drug Targeting; Flow Cytometry; Genetic Engineering; Goals; Hematopoietic; Human; Immune; Immune response; Immunosuppressive Agents; Immunotherapy; Knowledge; MAP Kinase Gene; Modeling; Molecular; Mus; Oncogenic; Pathway interactions; Patients; Regimen; Regulatory Pathway; Resistance; Resistance development; Role; Sampling; Therapeutic; Tissues; Toxic effect; Tumor Immunity; base; immunopathology; inhibitor/antagonist; insight; melanoma; mutant; novel; novel diagnostics; novel therapeutics; repository; resistance mechanism; response; tumor; tumor growth; tumor microenvironment; validation studies

Project 2 will investigate the role of immune responses in dictating the course of BRAF mutant melanoma and how such knowledge can be exploited to develop effective combination therapeutic regimen(s) based on synergy between immunomodulatory molecules and drugs targeting oncogenic BRAF. Expression of immunoregulatory molecules associated with responsiveness and resistance to BRAF-targeted therapy in human and murine melanoma will be determined using molecular, immunohistologic and flow cytometry approaches. Because of the recent therapeutic promise of anti-CTLA-4 therapy in melanoma. Project 2 also will analyze how ahti-CTLA-4 therapy alters the tumor microenvironment in samples from patients with melanoma treated with this immune checkpoint modulator. Functional and clinical validation studies of immunomodulatory targets in BRAF-mutant melanoma initially will determine how BRAF-targeted therapy impacts anti-tumor immunity using human PBMCs and TILs from treated patients and IBIP mice in the settings of responsiveness and resistance to BRAF therapy. Further studies will explore the impact of blocking immunomodulatory targets individually and in combination therapeutic strategies with BRAF-targeted therapy on tumor regression and anti-tumor immunity. Initial functional studies will focus on the CTLA-4 and PD-1/PDL pathways because of their potent immunomodulatory effects in melanoma. This detailed characterization of the immune response in BRAF mutant human and mouse melanomas during tumor growth, treatment and resistance will provide molecular insights into the immune components of BRAF-targeted therapy and guide development of rational combinations of BRAF-targeted therapy and immunotherapy to minimize resistance and achieve durable remission.

项目2将研究免疫反应在决定BRAF过程中的作用 突变型黑色素瘤以及如何利用这些知识开发有效的联合治疗 基于免疫调节分子和靶向致癌BRAF的药物之间的协同作用的方案。 免疫调节分子的表达与BRAF靶向治疗的反应性和耐药性相关 将使用分子、免疫组织学和免疫组织化学方法来确定人和鼠黑色素瘤的治疗。 流式细胞术方法。由于抗CTLA-4疗法在黑色素瘤中的最新治疗前景。 项目2还将分析AHTI-CTLA-4治疗如何改变肿瘤样本中的肿瘤微环境。 用这种免疫检查点调节剂治疗的黑素瘤患者。功能和临床确认 BRAF突变黑色素瘤免疫调节靶点的研究最初将确定BRAF如何靶向 使用来自治疗患者和IBIP小鼠的人PBMC和TIL， 对BRAF治疗的反应性和抵抗性的设置。进一步的研究将探讨 单独阻断免疫调节靶点以及与BRAF靶向药物联合治疗策略 肿瘤消退和抗肿瘤免疫的治疗。初步的功能研究将集中在 CTLA-4和PD-1/PDL通路，因为它们在黑色素瘤中具有强效免疫调节作用。这 BRAF突变的人和小鼠黑色素瘤中免疫应答的详细表征 肿瘤的生长、治疗和耐药性将提供对肿瘤免疫成分的分子见解， BRAF靶向治疗，并指导BRAF靶向治疗和 免疫疗法以最大限度地减少耐药性并实现持久缓解。