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: 9978748
• 负责人: Michael Davies
• 金额: $ 212.8万
• 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/9978748
• 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.

总体而言：项目摘要/摘要 黑色素瘤是最致命的皮肤癌，其发病率和死亡率不断增加，并且 5 年发病率 最近一些具有里程碑意义的基因组和转移性疾病患者的生存率低于 20%。 免疫学研究对疾病的发病机制、驱动因素和调节因素产生了重要的新见解。 这种疾病，转化为针对转移性患者的靶向疗法和免疫疗法的批准 虽然靶向治疗取得了很高的缓解率，但它们通常也是短暂的； 免疫疗法能带来显着的、长期的、完全的反应，但只在一小部分患者中有效 尽管已经取得了进展，但仍然存在一些关键挑战。 最大化免疫疗法的临床益处：1）对免疫疗法的标志物和机制知之甚少 对免疫治疗产生耐药性，并且缺乏有效的策略来克服它们；2）经验有限； 中枢神经系统受累患者的疗效，中枢神经系统受累是常见的转移部位和死亡原因 黑色素瘤和其他癌症；3）单药免疫疗法对患有以下疾病的患者没有任何益处： 非皮肤黑色素瘤，特别是葡萄膜黑色素瘤亚型 该 SPORE 的中心假设。 建议对晚期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耐药性的理解，并导致 为了检验这一假设，我们将重点关注最关键的未满足需求。 黑色素瘤患者，以当前的免疫治疗策略为基础，开发我们自己的新型免疫治疗策略 通过追求以下具体目标来确定更有效的治疗方案的概念： • 通过抑制 PTEN-中的 PI3K 通路来解决对 PD-1 免疫检查点抑制剂的耐药性 无转移性黑色素瘤患者（项目 1）。 • 确定使用鞘内注射纳武单抗治疗转移性肿瘤的 PD-1 阻断的临床效用 患有软脑膜疾病的黑色素瘤患者（项目 2）。 • 评估葡萄膜黑色素瘤的新治疗策略，该策略使用过继细胞疗法来靶向 黑素体转运蛋白 SLC45A2 的免疫原性表位（项目 3）。 三个核心（管理核心、临床数据库、组织资源和转化病理学核心 [核心 2] 和生物统计学和生物信息学核心 [核心 3]）提供专业服务来支持我们的 SPORE 研究者和他们提出的研究一起，这三个项目和核心以及我们的研究。 发展研究和职业提升计划将对关键的问题进行全面的攻击 与这些致命的黑色素瘤表现作斗争的患者的未满足的需求，并为其他治疗铺平了道路 治疗选择有限的癌症。