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

基本信息

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
项目类别：
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

项目摘要

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将调查免疫反应在决定BRAF过程中的作用突变黑色素瘤以及如何利用这种知识来发展有效的组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。与反应性和对BRAF靶向的抗性相关的免疫调节分子的表达人类和鼠类黑色素瘤的治疗将使用分子，免疫组织学和流式细胞仪接近。由于最近对黑色素瘤抗CTLA-4治疗的治疗有望。项目2还将分析AHTI-CTLA-4治疗如何改变来自样品的样品中的肿瘤微环境黑色素瘤患者用该免疫检查点调节剂治疗。功能和临床验证 BRAF突变剂黑色素瘤中免疫调节靶标的研究最初将确定BRAF靶向治疗使用人类PBMC和TIL在治疗患者和IBIP小鼠中影响抗肿瘤免疫力反应能力和抵抗BRAF治疗的设置。进一步的研究将探讨通过BRAF靶向分别和结合治疗策略，阻止免疫调节靶肿瘤回归和抗肿瘤免疫的治疗。最初的功能研究将集中于 CTLA-4和PD-1/PDL途径由于它们在黑色素瘤中的有效免疫调节作用。这 BRAF突变体和小鼠黑色素瘤中免疫反应的详细表征肿瘤的生长，治疗和抗性将提供分子见解 BRAF靶向疗法和指导BRAF靶向疗法的合理组合的发展免疫疗法以最大程度地减少抵抗力并实现持久的缓解。