NextGen - CRI

下一代 - CRI

• 批准号: 10627010
• 负责人: Catherine M. Bollard
• 金额: $ 87.12万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 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/10627010
• 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.

儿童癌症的下一代T细胞疗法[NextGen] 当前的治疗方法无法治愈许多患有固体癌症的儿童。成年癌症（例如检查点封锁和靶向小分子）的最新进展对儿童疾病的影响很小。工程的T细胞疗法可以在没有长期毒性的情况下实现难治性淋巴癌的持久反应。这些正是小儿固体癌症新疗法所需的特征。与血液学恶性肿瘤相反，由于缺乏靶标，肿瘤异质性和敌对的肿瘤微环境（TME），固体癌症挑战。我们认为，通过先进的蜂窝工程，我们可以克服这些挑战。我们的愿景是，用于儿童固体癌症的工程T细胞疗法将在十年内常规。我们的中心假设是，晚期细胞工程的耦合以及进行性临床发育是开发有效的小儿实体瘤T细胞疗法的最快途径。在NextGen中，我们结合了原发性肿瘤的详细研究，以发现新靶标，并了解TME如何颠覆T细胞功能。这以及紧密耦合的临床开发计划将指导T细胞的渐进工程，从而导致变革性疗法。 NextGen由6个相互连接的工作包（WPS）组成，最初专注于小儿肉瘤和脑肿瘤。目的：WP1：确定用于工程T细胞的合适目标。 WP2：了解小儿固体癌症中的TME。 WP3：开发靶向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T细胞的功能。 WP5：转化WP4的方法并在旨在最大影响的临床研究中测试它们。癌症的挑战 - 完整应用-2021 WP6：促进所有WPS的数据共享。方法：目标发现（WP1）和TME研究（WP2）将分别利用质谱和芯片细胞术。组件工程（WP3）将使用蛋白质工程方法。为了建模工程细胞功能，WP4将主要使用完整的肿瘤模型，例如免疫PDX。在WP5中，临床产品的产生将涉及自体封闭系统半自动制造。 WP6使用标准和自定义数据库以及数据共享平台。结果的使用：WP1和2的肿瘤目标和TME数据将上传到由WP6开发的数据库中，以进行广泛的分布。 WP3和WP4的功能数据的工程组件将由整个社区纳入治疗性T细胞策略。来自WP5的临床研究数据应导致注册研究，提高治愈率和缓解长期毒性以实现我们的视力。