Next Generation Cancer Immunotherapies to Defeat Melanoma

击败黑色素瘤的下一代癌症免疫疗法

• 批准号: 10518843
• 负责人: ANTONI RIBAS
• 金额: $ 93.6万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-09 至 2029-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518843
• 关键词: Adoptive Cell Transfers; Antigen Presentation; Antigens; Antitumor Response; Area; BRAF gene; Back; Bioinformatics; Biological Models; Biopsy; CRISPR screen; Cell Line; Cell physiology; Clinical; Clinical Trials; Combined Modality Therapy; Drug Screening; Engineered Gene; Exposure to; Functional disorder; Funding; Genes; Genetic; Immunotherapy; Interferon Type II; Knock-out; Knowledge; MEKs; Melanoma Cell; Methods; Pathway Analysis; Patients; Pharmacology; Resistance; Science; Shapes; Signal Pathway; T cell therapy; T-Cell Receptor; T-Lymphocyte; Testing; anti-PD-1; anti-tumor immune response; base; cancer cell; cancer immunotherapy; combinatorial; cytokine; data modeling; immune checkpoint blockade; improved; in vivo; inhibitor; loss of function mutation; melanoma; mouse model; next generation; novel therapeutics; programmed cell death ligand 1; programs; repository; response; targeted treatment; transcription factor

PROJECT SUMMARY / ABSTRACT This is a Type 2 renewal application aimed at building on the progress over the initial funding period to develop new therapies for patients with melanoma and studying the mechanistic basis of response and resistance to melanoma immunotherapies. We made significant progress in the three scientific areas of the initial funding period. We defined genetic mechanisms of primary and acquired to immune checkpoint blockade (ICB) through loss of function mutations in the antigen presenting machinery and the interferon-gamma (IFN-g) signaling pathway, which led us to successfully test combination therapies in mouse models and bring them back to patients in ongoing clinical trials. In the scientific area of combinatorial approaches of immunotherapy and targeted therapy, our mouse model data provided the justification for three triple therapy (BRAF plus MEK inhibitors and anti-PD-1 or -PD-L1) clinical programs, one of them resulting in an FDA approval. In the scientific theme of advancing gene engineered adoptive cell transfer (ACT) therapies, we have conducted three clinical trials, developed optimized means to isolate T cell receptors (TCRs), helped develop an approach for non-viral T cell gene editing, and develop approaches to provide superior cytokine support for in vivo T cell expansion. The new R35 proposal has three themes. Theme 1 is centered on how cancer cells are recognized or escape T cells, focusing on the antigen presentation machinery. It will use a repository of 1,031 already collected biopsies that will be analyze using newly developed methods of isolation, sequencing and bioinformatics analyses. Theme 2 is based on the key role of IFN-g in shaping an antitumor immune response; the realization that this cytokine turns the cancer cells into enablers of the antitumor immune response provides opportunities for exploiting the knowledge to improve immunotherapies. This will be achieved using CRISPR and drug screens in a panel of melanoma cell lines, followed by pathway analyses and mechanistic studies hopefully leading to new pharmacological targets to improve IFN-g antitumor activity. Theme 3 is focused on the T cell function and target recognition, and in particular in avoiding T cell dysfunction upon repeated antigen exposure, which is a major limitation to long term antitumor responses. This project will use CRISPR screens in T cells undergoing repeated antigen exposure to find genes that, when knocked-out, result in superior ability of T cells to maintain their functionality upon repeated TCR engagement. Furthermore, we will analyze the transcription factors that guide a superior in vivo expansion and antitumor activity of adoptively transferred T cells. In conclusion, the new R35 proposal builds on the science from the current OIA. We propose to use state-of- the-art approaches to analyze large numbers of patient biopsies, use CRISPR screens for mechanistic analyses and use model systems to improve responses and treat resistance to cancer immunotherapies. 1

项目概要/摘要 这是 2 类续签申请，旨在以初始资助期间的进展为基础，开发 黑色素瘤患者的新疗法并研究其反应和耐药的机制基础 黑色素瘤免疫疗法。我们在初始资金的三个科学领域取得了重大进展 时期。我们通过以下方式定义了原发性和获得性免疫检查点阻断（ICB）的遗传机制： 抗原呈递机制和干扰素-gamma (IFN-g) 信号传导功能突变丧失 途径，这使我们成功地在小鼠模型中测试了联合疗法并将其带回到 正在进行临床试验的患者。在免疫治疗和组合方法的科学领域 靶向治疗，我们的小鼠模型数据提供了三种三联疗法（BRAF 加 MEK 抑制剂和抗 PD-1 或​​ -PD-L1）临床项目，其中一项获得 FDA 批准。在科学上 以推进基因工程过继细胞移植（ACT）疗法为主题，我们进行了三项临床 试验，开发了分离 T 细胞受体 (TCR) 的优化方法，帮助开发了一种治疗非病毒的方法 T 细胞基因编辑，并开发为体内 T 细胞扩增提供卓越细胞因子支持的方法。 新的R35提案有三个主题。主题 1 围绕癌细胞如何被识别或逃避 T 细胞，重点关注抗原呈递机制。它将使用包含 1,031 个已收集的活检样本的存储库 将使用新开发的分离、测序和生物信息学分析方法对其进行分析。主题 2 基于 IFN-g 在形成抗肿瘤免疫反应中的关键作用；认识到这种细胞因子 将癌细胞转变为抗肿瘤免疫反应的推动者，为利用 改善免疫疗法的知识。这将通过一系列的 CRISPR 和药物筛选来实现 黑色素瘤细胞系，随后进行途径分析和机制研究，有望带来新的结果 提高 IFN-g 抗肿瘤活性的药理学靶点。主题 3 重点关注 T 细胞功能和靶标 识别，特别是避免重复接触抗原后 T 细胞功能障碍，这是一个主要的 长期抗肿瘤反应的限制。该项目将在 T 细胞中使用 CRISPR 筛选，进行重复 暴露于抗原以寻找基因，这些基因在被敲除后会导致 T 细胞保持其正常状态的卓越能力 重复 TCR 接合后的功能。此外，我们将分析指导的转录因子 过继转移的 T 细胞具有优异的体内扩增和抗肿瘤活性。 总之，新的 R35 提案建立在当前 OIA 的科学基础上。我们建议使用state-of- 分析大量患者活检的最先进方法，使用 CRISPR 筛选进行机械分析 并使用模型系统来改善癌症免疫疗法的反应和治疗耐药性。 1