The University of Texas MD Anderson Cancer Center SPORE in Melanoma

德克萨斯大学 MD 安德森癌症中心 SPORE 黑色素瘤

• 批准号: 10415934
• 负责人: Michael Davies
• 金额: $ 205.87万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-16 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10415934
• 关键词: Address; Adjuvant; Adoptive Cell Transfers; Adult; Affinity; Bioinformatics; Biometry; Carrier Proteins; Cause of Death; Cessation of life; Clinical; Clinical Research; Clinical Trials; Common Neoplasm; Communication; Community Health; Cutaneous Melanoma; Cytotoxic T-Lymphocytes; Data Analyses; Development; Disease; Distant Metastasis; Ensure; Epitopes; Eye Neoplasms; Faculty; Funding; Future; Genomics; Goals; Immune; Immune checkpoint inhibitor; Immune response; Immunologics; Immunology; Immunotherapeutic agent; Immunotherapy; In complete remission; Incidence; Investigation; Knowledge; Lead; Left; Malignant Neoplasms; Mentors; Metastatic Melanoma; Metastatic Neoplasm to the Central Nervous System; Molecular; Molecular Biology; Neuraxis; Nivolumab; Non-Cutaneous Melanoma; Outcome; PD-1 blockade; PTEN gene; Pathogenesis; Pathology; Pathway interactions; Patients; Pilot Projects; Population; Refractory; Research; Research Personnel; Resistance; Resources; Safety; Service provision; Services; Site; Skin Cancer; Survival Rate; Testing; Therapeutic; Toxic effect; Translating; Translational Research; Treatment Failure; University of Texas M D Anderson Cancer Center; Uveal Melanoma; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; burden of illness; career; clinical database; clinical investigation; combinatorial; data sharing; design; effective therapy; experience; experimental study; global health; immunogenic; improved; insight; meetings; melanoma; microbiome; mortality; multidisciplinary; novel; novel strategies; novel therapeutic intervention; novel therapeutics; patient subsets; programmed cell death protein 1; programs; research study; resistance mechanism; response; targeted treatment; therapy resistant; tissue resource; treatment site; treatment strategy; tumor

Overall: Project Summary/Abstract Melanoma is the deadliest form of skin cancer, with an increasing incidence and mortality, and a 5-year survival rate less than 20% for patients with metastatic disease. Several recent landmark genomic and immunologic studies have generated important new insights into the pathogenesis, drivers, and regulators of this disease, translating into the approval of both targeted and immune therapies for patients with metastatic disease. While targeted therapies have achieved high response rates, they are generally transient; likewise, immunotherapies bring about dramatic, long-term, complete responses but only in a subset of patients and often with serious toxicities. Despite the progress that has been made, several key challenges remain to maximizing the clinical benefit of immunotherapy: 1) poorly understood markers and mechanisms of resistance to immunotherapy, and a lack of effective strategies to overcome them; 2) limited experience or efficacy in patients with central nervous system involvement, a common metastatic site and cause of death for melanoma and other cancers; and 3) lack of any benefit from single-agent immunotherapies in patients with non-cutaneous melanomas, particularly the uveal melanoma subtype. The central hypothesis of this SPORE proposal is that an integrated analysis of immune and molecular features in patients with advanced melanoma will improve our understanding of response and resistance to immunotherapy, and lead to more effective treatments. To test this hypothesis, we will focus on the most critical unmet needs of melanoma patients, building on current immunotherapeutic strategies and developing our own novel concepts to identify more effective treatment options by pursuing the following specific aims: • Address resistance to the PD-1 immune checkpoint inhibitor through inhibition of the PI3K pathway in PTEN- null metastatic melanoma patients (Project 1). • Determine the clinical utility of PD-1 blockade using nivolumab administered intrathecally in metastatic melanoma patients with leptomeningeal disease (Project 2). • Evaluate a new therapeutic strategy for uveal melanoma that uses adoptive cell therapy to target an immunogenic epitope of melanosomal transport protein SLC45A2 (Project 3). Three cores (Administrative Core, Clinical Database, Tissue Resource, and Translational Pathology Core [Core 2] and Biostatistics and Bioinformatics Core [Core 3]) provide specialized services to support our SPORE investigators and their proposed research studies. Together, these three projects and cores and our Developmental Research and Career Enhancement Programs will provide a comprehensive attack on critical unmet needs for patients battling these deadly manifestations of melanoma, and pave the way for other cancers with limited therapeutic options.

总体：项目摘要/摘要 黑色素瘤是皮肤癌最致命的形式，发病率和死亡率越来越高，5年 转移性疾病患者的存活率小于20％。最近的一些具有里程碑意义的基因组和 免疫学研究已经对发病机理，驱动因素和调节剂产生了重要的新见解。 这种疾病，转化为转移患者的靶向和免疫疗法的批准 疾病。尽管有针对性的疗法达到了很高的缓解率，但它们通常是短暂的。同样地， 免疫疗法带来了戏剧性的，长期的完整反应，但仅在一部分患者和 通常具有严重的毒性。尽管取得了进展，但仍有一些关键挑战 最大化免疫疗法的临床益处：1）不良理解标记和机制 对免疫疗法的抵抗力，以及缺乏克服这些免疫疗法的有效策略； 2）有限的经验或 中枢神经系统参与患者的功效，常见的转移性部位和死亡原因 黑色素瘤和其他癌症； 3）患者的单药免疫疗法缺乏任何好处 非皮肤黑色素瘤，尤其是卵子黑色素瘤亚型。该孢子的中心假设 建议是对患者的免疫和分子特征进行综合分析 黑色素瘤将提高我们对免疫疗法的反应和抵抗力的理解，并导致 更有效的治疗方法。为了检验这一假设，我们将专注于最关键的未满足需求 黑色素瘤患者，基于当前的免疫治疗策略并发展我们自己的小说 通过追求以下特定目的来识别更有效的治疗方案的概念： •通过抑制PTEN-的PI3K途径来解决对PD-1免疫抑制剂抑制剂的抗性 无效转移性黑色素瘤患者（项目1）。 •使用固定的转移性施用的Nivolumab确定PD-1阻滞的临床实用性 黑色素瘤患者患有瘦脑脑疾病（项目2）。 •评估一种使用自适应细胞疗法的紫美黑色素瘤的新理论策略 黑色素体转运蛋白SLC45A2的免疫原性发作（项目3）。 三个核心（行政核心，临床数据库，组织资源和翻译病理核心 [核心2]以及生物统计学和生物信息学核心[核心3]）提供专门的服务来支持我们的孢子 研究人员及其拟议的研究。这三个项目和核心在一起，我们 发展研究和职业增强计划将对关键的全面攻击 未满足的患者对这些致命的黑色素瘤表现的战斗，并为其他人铺平道路 治疗选择有限的癌症。