Allogeneic Chondroprogenitor Therapy (Phase II) (ACT2)

在英国，大约有411万人患有膝骨关节炎。因此，2016年进行了98,147次全膝关节置换术，花费5.1亿英镑，六年内增长了33%。每年约有10万至1.6万人需要治疗软骨缺损，如果不治疗，可能会发展为OA。通过有效的早期治疗，OA是可以预防的。国家临床卓越研究所（NICE）指出，最具成本效益的软骨修复治疗是自体软骨细胞植入（ACI）。ACI是一种用于治疗膝关节软骨缺损的两阶段手术：首先进行膝关节镜检查（锁眼手术），然后进行软骨活检。然后从活检中提取患者自身（自体）软骨细胞（软骨细胞）并在实验室中培养。在4 ~ 6周后的第二次手术中，将细胞植入软骨缺损。NICE于2017年10月批准了ACI，但由于监管限制和自体产品的挑战，NHS中心几乎没有采用ACI。软骨细胞通常不会在体内繁殖，当在实验室中繁殖时，它们会失去产生软骨的能力，这是一些ACI失败的一个潜在原因。然而，软骨中有一种叫做软骨祖细胞（CPs）的细胞亚群，其行为更像干细胞，能够在不影响其功能的情况下繁殖多次。我们计划使用器官捐献者捐献的软骨组织来获得CPs，然后将其繁殖并在一次手术中植入软骨缺损。因此，许多病人可以从一个供体得到治疗。与标准ACI相比，这可以简化NHS的采用，提高患者的可及性并以更具成本效益的方式降低发病率。该项目的主要目标是：1：优化CP制造工艺：首先，我们将建立安全有效的NHSBT供体软骨供应。目前的生产过程将被优化，并通过去除动物源试剂来保证未来的安全性。这将确保将方法有效地转移到伯明翰的制造工厂（ATF）。制作完成后，细胞将被冷冻保存。然后，我们需要确定在不影响细胞功能的情况下，我们能储存这些细胞多长时间。将确认电池的初始保质期为6个月，并在整个项目中进行持续测试，以确定电池的最长储存时间。质量保证测试将最终确定，以确保提供的细胞是一致和有效的。在将方案转移到ATF之前，制造过程将由细胞和基因治疗弹射器独立审查，以确保该过程中没有可能阻碍临床试验进展和未来商业化的明显缺陷。2：项目第一阶段优化的细胞制造方法将转移到ATF，在严格的临床条件下进行进一步的验证试验。将获得MHRA和伦理机构所需的许可，以便我们进行临床试验。3：一项20名患者的试验，研究同种异体软骨祖细胞治疗膝关节孤立软骨病变将在3个中心进行：伯明翰皇家骨科医院；罗伯特·琼斯和艾格尼丝·亨特骨科医院，奥斯韦斯特和纳菲尔德骨科中心，牛津。主要结局指标将是术后3、6、9和12个月的安全性和患者报告的结局评分。次要结果将是12个月时MRI扫描的修复组织数量和质量。我们希望这个项目能够解决英国目前未满足的患者需求，并作为未来同种异体细胞疗法发展的典范。

In the UK, approximately 4.11 million people have knee osteoarthritis (OA). Consequently 98,147 total knee replacements were performed in 2016 costing £510 million, a rise of 33% in 6 years. Around 10-16,000 people require treatment for cartilage defects every year, which if untreated, can progress to OA. With effective early treatment, OA could be prevented.The National Institute for Clinical Excellence (NICE) have stated that the most cost-effective treatment for cartilage repair is autologous chondrocyte implantation (ACI). ACI is a 2-stage process used to treat cartilage defects in the knee: an initial knee arthroscopy (key-hole surgery) is performed and a cartilage biopsy obtained. The patient's own (autologous) cartilage cells (chondrocytes) are then extracted from the biopsy and grown in the laboratory. The cells are implanted in the cartilage defect at a second surgery ~4 to 6 weeks later. NICE approved ACI in Oct-17, but there has been little adoption by NHS centres due to the regulatory constraints and challenges of an autologous product.Chondrocytes typically do not multiply in the body and when made to do so in the lab can lose their ability to produce cartilage, one potential reason for some ACI failures. However, there is a subpopulation of cells in cartilage called Chondroprogenitors (CPs) which behave more like stem cells and have the ability to be multiplied many times over without affecting their function. We plan to use donated cartilage tissue from organ donors to obtain CPs, which will then be multiplied and implanted into cartilage defects in a single surgery. Consequently, many patients could be treated from a single donor. This could streamline NHS adoption, improve patient access & reduce morbidity in a more cost-effective way compared to standard ACI.Key objectives of the project are:1: Optimise CP manufacture process: Initially we will establish a safe and effective supply of donor cartilage from NHSBT. The current manufacture process will then be optimised and future proofed by removing animal sourced reagents. This will ensure efficient transfer of methodologies to the manufacturing facility (ATF) in Birmingham. Following manufacture, the cells will be frozen and stored. We will then need to determine how long we will be able to store the cells without compromising their function. An initial 6-month shelf life of the cells will be confirmed, with continued tests on-going throughout the project in order to determine the cells' maximum storage time. Quality assurance tests will be finalised to ensure the cells provided are consistent and potent. Prior to transferring protocols to the ATF the manufacture process will be independently reviewed by the Cell and Gene Therapy Catapult so as to ensure there are no apparent flaws in the process that may prevent progression to the clinical trial and future commercialisation.2: The optimised method of cell manufacture from phase 1 of the project will be transferred to the ATF for further confirmatory tests under strict clinical conditions. The licences required from the MHRA and ethical bodies will be obtained in order for us to proceed to the clinical trial.3: A 20 patient trial to investigate allogeneic chondroprogenitors for the treatment of isolated cartilage lesions in the knee will be performed in 3 centres: The Royal Orthopaedic Hospital, Birmingham; The Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry and The Nuffield Orthopaedic centre, Oxford. The primary outcome measure will be safety and Patient Reported Outcome Scores, at 3, 6, 9 & 12 months post-operatively. Secondary outcomes will be repair tissue quantity & quality on MRI scans at 12 months.We hope that this project will address a current unmet patient need within the UK and serve as an exemplar for the development of future allogeneic cell therapies.