Optimization of the potency and specificity of engineered regulatory t cells to treat inflammatory and fibrotic liver diseases

优化工程调节性 T 细胞治疗炎症和纤维化肝病的效力和特异性

• 批准号: 2886706
• 金额: --
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2886706
• 关键词: Optimization; potency; specificity; engineered; regulatory

The prevalence of chronic liver disease, the 5th most common cause of death in the UK is rising sharply mainly due to the increasing load of viral hepatitis, alcohol- related liver disease and non-alcoholic fatty liver. This increasing burden of liver disease in the UK is in stark contrast to the vast improvements made in health and life expectancy for other chronic disorders and most cancers. There is a pressing need therefore to find novel modalities of treatment to prevent or halt liver disease progression, which unabated leads to complications such as portal hypertension, cancer and ultimately death. Although the molecular and cellular events underlying the progression of liver disease remain poorly understood, dysregulated local and systemic inflammatory responses are involved in amplifying hepatic injury and fibrogenesis, which leads to clinical decompensation and death. In this regard, patients with advanced forms of liver disease have been shown to exhibit multiple innate and adaptive immune deficits. As previously reported in autoimmune hepatitis and primary sclerosing cholangitis, this includes reductions in the number and function of CD4+Foxp3+ regulatory T cells (Tregs), which are a lymphocyte subset that is essential for the maintenance of immunological tolerance and that has the capacity to migrate to sites of inflammation and exert powerful anti-inflammatory, tissue repair and regenerative properties. The prospect of ameliorating immunopathology in chronic inflammatory diseases and re-establishing tolerance in autoimmunity and transplantation, has prompted a growing interest in the development of Treg-based cell therapies. This is despite critical gaps in knowledge regarding how the inflammatory microenvironment controls Treg trafficking, activation, longevity, stability, and suppressive function in vivo. King's College London has pioneered the use of ex vivo expanded Treg adoptive transfer. Our clinical trials using non-engineered autologous polyclonal Tregs in kidney (ONE and TWO Studies, Gamechanger) and liver transplantation (THRIL) have demonstrated the safety of ex vivo expanded non-engineered polyclonal Treg transfer and provided encouraging evidence for their biological efficacy. However, the limited control over Treg trafficking, potency and longevity means that this strategy is unlikely to fulfil the promise of Treg immunotherapy as a truly transformative cell therapy. Chimeric antigen receptors (CARs) and gain-of-function genetic engineering provide unique opportunities to reprogram Tregs to address the limitations outlined above. We and others have generated HLA-A2-specific CAR human Tregs and shown their trafficking to organs expressing HLA-A2 with superior anti-inflammatory effects as compared to polyclonal Tregs. These results have generated considerable interest in the use of CAR-Tregs in humans, and a clinical trial sponsored by our spin-off company Quell Therapeutics employing anti-HLA-A2 CAR-Tregs in liver transplantation is currently underway (LIBERATE, NCT05234190). Anti-HLA-A2 CAR-Tregs, however, can only benefit HLA-A2-negative transplant recipients who have received an HLA-A2-positive liver. There is a need therefore to generate organ- rather than allo-antigen specific CAR-Tregs to treat non-transplant liver patients. We propose now to create a human next generation modular CAR-Treg product specifically designed to treat inflammatory and fibrotic liver diseases

慢性肝病是英国第五大最常见死因，其患病率正在急剧上升，主要原因是病毒性肝炎、酒精相关性肝病和非酒精性脂肪肝的数量不断增加。英国日益增加的肝病负担与其他慢性疾病和大多数癌症的健康和预期寿命的巨大改善形成鲜明对比。因此，迫切需要找到新的治疗方式来预防或阻止肝病进展，肝病进展有增无减，导致门静脉高压、癌症等并发症，并最终导致死亡。尽管对肝病进展背后的分子和细胞事件仍知之甚少，但局部和全身炎症反应失调会加剧肝损伤和纤维形成，从而导致临床失代偿和死亡。在这方面，晚期肝病患者已被证明表现出多种先天性和适应性免疫缺陷。正如之前在自身免疫性肝炎和原发性硬化性胆管炎中所报道的，这包括 CD4+Foxp3+ 调节性 T 细胞 (Treg) 的数量和功能减少，Treg 是淋巴细胞亚群，对于维持免疫耐受至关重要，并且能够迁移到炎症部位并发挥强大的抗炎、组织修复和再生特性。改善慢性炎症性疾病的免疫病理学以及重建自身免疫和移植耐受性的前景促使人们对开发基于 Treg 的细胞疗法越来越感兴趣。尽管关于炎症微环境如何控制体内 Treg 运输、激活、寿命、稳定性和抑制功能的知识还存在重大差距。伦敦国王学院率先使用离体扩展的 Treg 过继转移。我们在肾脏（一项和两项研究，Gamechanger）和肝移植（THRIL）中使用非工程化自体多克隆 Treg 进行的临床试验证明了离体扩增非工程化多克隆 Treg 移植的安全性，并为其生物学功效提供了令人鼓舞的证据。然而，对 Treg 运输、效力和寿命的有限控制意味着该策略不太可能实现 Treg 免疫疗法作为真正变革性细胞疗法的承诺。嵌合抗原受体 (CAR) 和功能获得性基因工程为重新编程 Tregs 提供了独特的机会，以解决上述局限性。我们和其他人已经生成了 HLA-A2 特异性 CAR 人类 Tregs，并显示它们被运输到表达 HLA-A2 的器官，与多克隆 Tregs 相比，具有更好的抗炎作用。这些结果引起了人们对在人类中使用 CAR-Tr​​eg 的极大兴趣，由我们的衍生公司 Quell Therapeutics 赞助的一项在肝移植中使用抗 HLA-A2 CAR-Tr​​eg 的临床试验目前正在进行中（LIBERATE，NCT05234190）。然而，抗 HLA-A2 CAR-Tr​​eg 只能使接受 HLA-A2 阳性肝脏的 HLA-A2 阴性移植受者受益。因此，需要产生器官特异性而非同种异体抗原特异性的 CAR-Tr​​eg 来治疗非移植肝患者。我们现在建议创建一种人类下一代模块化 CAR-Tr​​eg 产品，专门用于治疗炎症和纤维化肝病