NexTGen - ICR

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，如检查点封锁和靶向小分子，对儿童疾病几乎没有影响。基因工程T细胞疗法可以在难治性淋巴癌中取得持久的反应，而不会产生长期毒性。这些正是儿童实体癌新疗法所需要的特征。与血液系统恶性肿瘤相比，实体癌由于缺乏靶点、肿瘤的异质性和恶性的肿瘤微环境(TME)而具有挑战性。我们假定，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，工程T细胞疗法将在十年内成为儿童实体癌症的常规疗法。我们的中心假设是，结合先进的细胞工程和不断进步的临床发展，是开发有效的儿童实体瘤T细胞疗法的最快途径。在NextGen中，我们结合了对原发肿瘤的详细研究，以发现新的靶点，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将指导T细胞的进步工程，以产生变革性的治疗方法。NextGen由6个相互关联的工作包(WPS)组成，最初的工作重点是儿童肉瘤和脑瘤。目的：WP1：为工程化T细胞寻找合适的靶点。WP2：了解儿童实体肿瘤的TME。WP3：开发针对肿瘤细胞的受体和其他工程组件，并抵抗或调节TME。WP4：评价WP3培养的工程化T细胞的功能。WP5：翻译来自WP4的方法，并在为最大影响而设计的临床研究中测试它们。癌症大挑战-全面应用-2021年WP6：促进所有WP之间的数据共享。方法：靶点发现(WP1)和TME研究(WP2)将分别利用质谱学和芯片细胞术。组份工程(WP3)将使用蛋白质工程方法。为了模拟工程细胞的功能，WP4将主要使用完整的肿瘤模型，如免疫PDX。在WP5中，临床产品的产生将涉及自体封闭系统的半自动制造。WP6使用标准和定制的数据库和数据共享平台。结果的使用：来自WP1和2的肿瘤靶点和TME数据将被上传到WP6开发的数据库以供广泛分发。来自WP3的工程组件和来自WP4的功能数据将被整个社区纳入治疗T细胞策略。来自WP5的临床研究数据应该导致注册研究，提高治愈率和减轻长期毒性，以实现我们的愿景。

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.