NexTGen - STANFORD

NexTGen - 斯坦福

• 批准号: 10625700
• 负责人: IRVING L. WEISSMAN
• 金额: $ 73.05万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-22 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10625700
• 关键词: Text

Next Generation T cell therapies for childhood cancers [NexTGen] Current treatments fail to cure many children with solid cancers. Recent advances in adult cancers such as checkpoint blockade and targeted small molecules have made little impact in childhood disease. Engineered T-cell therapies can achieve durable responses in refractory lymphoid cancers without long-term toxicity. These are precisely the characteristics required for new treatments for pediatric solid cancers. In contrast to hematologic malignancies, solid cancers are challenging due to a lack of targets, tumor heterogeneity, and hostile tumor microenvironment (TME). We posit that through advanced cellular engineering we can overcome these challenges. Our vision is that engineered T-cell therapy for childhood solid cancers will become routine within a decade. Our central hypothesis is that coupling of advanced cellular engineering along with progressive clinical development is the fastest route to developing effective T-cell therapies for pediatric solid tumors. In NexTGen, we combine detailed studies of primary tumors to discover new targets and understand how the TME subverts T- cell function. This, along with a closely coupled clinical development program will guide the progressive engineering of T-cells to result in transformative therapies. NexTGen is composed of 6 inter-connected work-packages (WPs) with work initially focused on pediatric sarcomas and brain tumors. AIMS: WP1: To identify suitable targets for engineered T-cells. WP2: To understand the TME in pediatric solid cancers. WP3: To develop receptors and other engineering components which target tumor cells and resist or modulate the TME. WP4: To evaluate the function of engineered T-cells developed in WP3. WP5: To translate approaches from WP4 and test them in clinical studies designed for maximal impact. Cancer Grand Challenges - Full Application - 2021 WP6: To promote data sharing across all WPs. METHODS: Target discovery (WP1) and TME studies (WP2) will utilize mass spectroscopy and chip cytometry respectively. Component engineering (WP3) will use protein engineering methods. To model engineered cell function, WP4 will mostly use intact tumor models such as immune PDXs. In WP5, clinical product generation will involve autologous closed system semi-automated manufacturing. WP6 uses standard and custom databases and data sharing platforms. USE OF RESULTS: Tumor target and TME data from WP1 and 2 will be uploaded to databases developed by WP6 for widespread distribution. Engineering components from WP3 and functional data from WP4 will be available for incorporation into therapeutic T-cell strategies by the entire community. Clinical study data from WP5 should lead to registration studies, improving cure rates and mitigation of long-term toxicity to realize our Vision.

治疗儿童癌症的下一代 T 细胞疗法 [NexTGen] 目前的治疗方法无法治愈许多患有实体癌症的儿童。成人癌症的最新进展，例如检查点封锁和靶向小分子，对儿童疾病影响甚微。工程化 T 细胞疗法可以在难治性淋巴癌中实现持久反应，且无长期毒性。这些正是儿童实体癌新疗法所需的特征。与血液恶性肿瘤相比，实体癌由于缺乏靶点、肿瘤异质性和恶劣的肿瘤微环境（TME）而具有挑战性。我们认为，通过先进的细胞工程，我们可以克服这些挑战。我们的愿景是，针对儿童实体癌的工程 T 细胞疗法将在十年内成为常规疗法。我们的中心假设是，先进的细胞工程与渐进的临床开发相结合是开发有效的儿童实体瘤 T 细胞疗法的最快途径。在 NexTGen 中，我们结合对原发性肿瘤的详细研究来发现新靶点并了解 TME 如何颠覆 T 细胞功能。这与紧密结合的临床开发计划一起将指导 T 细胞的渐进工程，以实现变革性疗法。 NexTGen 由 6 个相互关联的工作包 (WP) 组成，最初的工作重点是儿科肉瘤和脑肿瘤。目标：WP1：确定工程 T 细胞的合适靶点。 WP2：了解儿科实体癌的 TME。 WP3：开发针对肿瘤细胞并抵抗或调节 TME 的受体和其他工程组件。 WP4：评估 WP3 中开发的工程化 T 细胞的功能。 WP5：转化 WP4 的方法并在旨在产生最大影响的临床研究中对其进行测试。癌症大挑战 - 全面应用 - 2021 WP6：促进所有 WP 之间的数据共享。方法：靶标发现 (WP1) 和 TME 研究 (WP2) 将分别利用质谱法和芯片细胞术。组件工程（WP3）将使用蛋白质工程方法。为了模拟工程细胞功能，WP4 将主要使用完整的肿瘤模型，例如免疫 PDX。在WP5中，临床产品的生成将涉及自体封闭系统半自动化制造。 WP6 使用标准和自定义数据库和数据共享平台。结果的使用：WP1 和 2 的肿瘤靶点和 TME 数据将上传到 WP6 开发的数据库中以供广泛分发。 WP3 的工程组件和 WP4 的功能数据将可供整个社区纳入治疗性 T 细胞策略。 WP5 的临床研究数据应导致注册研究，提高治愈率并减轻长期毒性，以实现我们的愿景。