FAST CAR-T: Faster, Adaptive and Scalable Technologies For CAR-T Manufacture

快速CAR-T：更快、适应性和可扩展的CAR-T制造技术背景：细胞和基因疗法（cgt）是一种变革性的新疗法，已经显示出显著的临床效果。临床上和商业上最先进的cgt是嵌合抗原受体T （CAR-T）细胞免疫疗法。CAR-T疗法是一种新型的个性化癌症治疗方法，用于治疗对化疗有抗药性的血癌患者，以及所有其他治疗方法都失败的患者。CAR - T细胞可以使以前被认为无法治愈的癌症患者的病情持续缓解。尽管有这样的临床前景，CAR-T疗法的成本可能超过30万英镑，因为制造的时间和复杂性，以及这些疗法的个性化性质，在生产和产品发布方面带来了前所未有的挑战。需要快速、自适应和可扩展的制造解决方案来降低生产成本，提高产品一致性，并改善患者对这种变革性、治愈性治疗方式的获取。愿景：我们的愿景是通过逐步改变CAR-T免疫疗法的开发和生产方式，为患者特异性疗法和未来的通用供体CAR-T疗法带来革命性的CAR-T生产。这将集中解决未来CAR-T制造的3个关键领域：(1)使患者特异性CAR-T疗法更快；(2)使制造过程适应患者的可变性；(3)使其可扩展以适应下一波异体（通用供体）CAR-T疗法。这将以对分散的、即时医疗制造的监管、运营和商业模式的关注为基础。总体目标：我们的目标是建立一个更快、更灵活的CAR-T生产流程，以加速制造和发布，并开发自适应数字工具和可扩展的流程，从而实现向自主制造的转变，并实现监管合规所需的相关控制，从而实现分散生产。此外，随着CAR-T领域科学的发展，异体（通用供体）CAR-T疗法开始出现。同种异体方法涉及使用健康的供体T细胞，而不像自体CAR - T细胞产品，它来源于个体患者样本，只能用于个体患者。因此，未来的通用供体CAR-T生产需要可扩展的制造解决方案。这一目标将通过完成四个工作包（WPs）来实现：WP1：开发为期2天的CAR-T制造工艺，实施改进和加速的CAR-T产品测试、发布和认证。WP2：创建数字工具，如数字双胞胎和流程模型，以实现自主、数字集成、抗干扰的CAR-T生产。WP3：通用供体CAR-T可扩展灌注式搅拌槽生物反应器工艺的开发。WP4：建立即时护理CAR-T制造的运营和商业模式以及监管环境。团队：FAST CAR-T涉及来自四个不同研究和临床组织的8名研究人员和5名博士后研究人员，包括伦敦大学学院、皇家自由医院、提赛德大学和布里斯托尔大学。所有学术合作伙伴都是与FAST CAR-T提案相关的各自研究领域的公认领导者，特别是CAR-T生物处理和GMP制造（UCL），生物系统分析，数字化和控制（Teesside）以及再分配制造和供应链创新（UWE）。通过我们的集体和共同努力，我们相信我们处于一个理想的位置，可以提供一个全面的、有凝聚力的、雄心勃勃的研究项目，并在CAR-T免疫疗法的开发和生产方面实现一个步骤的改变，无论是针对患者的治疗，还是未来的通用供体CAR-T治疗。

FAST CAR-T: Faster, Adaptive and Scalable Technologies for CAR-T ManufactureContext: Cell & gene therapies (CGTs) are transformative novel treatments which have demonstrated remarkable clinical outcomes. The most clinically and commercially advanced embodiment of CGTs are chimeric antigen receptor T (CAR-T) cellular immunotherapies. CAR-T therapy is a new type of personalised cancer treatment used to treat patients with blood cancers whose disease is resistant to chemotherapy and who have failed all other therapeutic options. CAR T cells can result in lasting remissions in patients with cancers previously considered incurable. Despite this clinical promise, CAR-T therapies can cost in excess of £300,000 due to the time and complexity of manufacture and the personalised nature of these therapies which introduce unprecedented challenges in their production and product release. Rapid, adaptive and scalable manufacturing solutions are required to reduce the cost of production, improve product consistency, and improve patient access to this transformative, curative therapeutic modality.Vision: Our vision is to revolutionise CAR-T production by delivering a step change in how CAR-T immunotherapies are developed and manufactured for both patient-specific therapies, and future universal donor CAR-T therapies. This will focus on addressing 3 key areas for future CAR-T manufacture: (1) make patient-specific CAR-T therapies faster (2) make the manufacturing process adaptive to accommodate patient variability, and (3) make it scalable to accommodate the next wave of allogeneic (universal donor) CAR-T therapies. This will be underpinned by a focus on the regulatory, operational and business models for decentralised, point-of-care manufacture.Overall Aim: We aim to establish a faster, more agile CAR-T production process for expedited manufacture and release and develop adaptive digital tools and scalable processes that enable the shift to autonomous manufacture with the associated controls needed for regulatory compliance to enable the decentralised production. Moreover, with the evolving science in the CAR-T sector, allogeneic (universal donor) CAR-T modalities are beginning to emerge. Allogeneic approaches involve the use of healthy donor T-cells, unlike autologous CAR T cell products, which are derived from individual patient samples and can be used in that individual patient only. Therefore, scalable manufacturing solutions are required for these future universal donor CAR-T production.This aim will be delivered through completion of four Work Packages (WPs):WP1: Development of a 2-day CAR-T manufacture process and implementation of an improved and expedited testing, release and certification of CAR-T products.WP2: Creation of digital tools, such as digital twins and process models, to enable autonomous, digitally-integrated, disruption-resilient CAR-T production.WP3: Development of scalable perfusion-based stirred-tank bioreactor process for universal donor CAR-T.WP4: Establishing the operational and business models, and regulatory environment for point-of-care CAR-T manufacture.Team: FAST CAR-T involves 8 investigators and 5 post-doctoral researchers across four different research and clinical organisations including UCL, Royal Free Hospital, University of Teesside and UWE Bristol. All academic partners are recognised leaders in their respective areas of research related to the FAST CAR-T proposal, specifically, CAR-T bioprocessing and GMP manufacture (UCL), biosystems analysis, digitalisation and control (Teesside), and redistributed manufacture and supply chain innovation (UWE). Through our collective and combined efforts, we believe we are ideally placed to deliver a comprehensive, cohesive and ambitious research programme, and deliver a step change in how CAR-T immunotherapies are developed and manufactured for both patient-specific therapies, and future universal donor CAR-T therapies.