Phase I/II clinical trial of autologous T cell gene therapy to treat X-linked lymphoproliferative disease (XLP)

自体T细胞基因疗法治疗X连锁淋巴增殖性疾病（XLP）的I/II期临床试验

• 批准号: MR/Y019458/1
• 负责人: Claire Booth
• 金额: $ 218.91万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY019458%2F1
• 关键词: Phase; II; clinical; trial; autologous

X-linked lymphoproliferative disease (XLP) is a rare genetic condition that affects boys. Symptoms vary but most patients have dangerous immune responses to some viral infections (called haemophagocytic lymphohistiocytosis or HLH),recurrent infections and about a third develop lymphoma. Affected boys become sick in childhood or early adolescence. At the moment, patients are often treated with lifelong immunoglobulin therapy and treatment of any malignancies or disease complications. We can offer bone marrow transplant as a treatment, but the results depend on having a well-matched donor and preferably transplant before complications develop. Up to 50% of patients with active disease transplanted from a mismatched donor will not survive after transplant. There is a clear unmet need for patients lacking a suitable transplant donor and alternative approaches are required to alleviate the burden of disease complications, prevent infections lifelong and reduce risks of malignancy and HLH. Most of the immune system abnormalities seen in this condition arise due to abnormal function of T cells. We have already shown using an XLP mouse model and through studies on XLP patient T cells that we can correct many of these abnormalities including immunoglobulin production, antibody responses to immune challenge and tumour formation through providing gene corrected T cells. We therefore believe that gene therapy of patients' T cells alone will help many of their symptoms and may be a safer treatment option than a bone marrow transplant from an unrelated donor. By using the patient's own cells we avoid any risk of graft versus host disease which can cause significant morbidity and mortality after transplant and we are able to use less chemotherapy than would be involved in a bone marrow transplant. As in other gene therapy clinical trials underway in our department, we will use a type of virus (a lentivirus) to transfer a normal copy of the defective gene into patient T cells. There have been no safety concerns associated with this type of virus or infusing patients with gene modified T cells (for example to treat specific forms of cancer).The aim of this proposal is an early-phase clinical trial of T cell gene therapy which may offer XLP patients a long-term treatment option. We seek funding to generate and test virus suitable for clinical use and perform a clinical trial at Great Ormond Street Hospital recruiting 7 patients. We plan to include patients over 1-year-old and under 18 years of age with a confirmed diagnosis of XLP. T cells will be collected, corrected and frozen to ensure we have sufficient gene-corrected cells to give back to the patient. Patients will be monitored to establish the safety and efficacy of the treatment focusing on the detection of gene-corrected cells and the ability to stop immunoglobulin therapy without infection risk. This will be the first trial of its kind for XLP and the T cell gene therapy approach outlined could be used to treat other immune disorders affecting T cells. We have extensive experience in delivering successful gene therapy trials for immune disorders and if we can show that this treatment is effective we will undertake a pivotal registration trial allowing a move towards licensing which would make this therapy more widely available.

X 连锁淋巴组织增生性疾病 (XLP) 是一种影响男孩的罕见遗传病。症状各不相同，但大多数患者对某些病毒感染（称为噬血细胞性淋巴组织细胞增多症或 HLH）、反复感染有危险的免疫反应，大约三分之一的患者会发展为淋巴瘤。受影响的男孩在童年或青春期早期患病。目前，患者通常接受终生免疫球蛋白治疗以及任何恶性肿瘤或疾病并发症的治疗。我们可以提供骨髓移植作为治疗方法，但结果取决于是否有匹配良好的供体，并且最好在出现并发症之前进行移植。从不匹配的供体移植而来的活动性疾病患者中，高达 50% 的患者在移植后将无法存活。缺乏合适移植供体的患者的需求明显未得到满足，需要替代方法来减轻疾病并发症的负担、终身预防感染并降低恶性肿瘤和 HLH 的风险。这种情况下出现的大多数免疫系统异常都是由于 T 细胞功能异常引起的。我们已经使用 XLP 小鼠模型并通过对 XLP 患者 T 细胞的研究表明，我们可以通过提供基因校正的 T 细胞来纠正许多异常，包括免疫球蛋白的产生、对免疫挑战的抗体反应和肿瘤形成。因此，我们相信仅对患者 T 细胞进行基因治疗将有助于缓解他们的许多症状，并且可能是比来自无关捐赠者的骨髓移植更安全的治疗选择。通过使用患者自身的细胞，我们可以避免任何移植物抗宿主病的风险，这种疾病可能导致移植后显着的发病率和死亡率，并且我们能够使用比骨髓移植更少的化疗。与我们部门正在进行的其他基因治疗临床试验一样，我们将使用一种病毒（慢病毒）将缺陷基因的正常副本转移到患者 T 细胞中。此类病毒或向患者输注基因修饰的 T 细胞（例如治疗特定形式的癌症）不存在任何安全问题。该提案的目的是 T 细胞基因疗法的早期临床试验，该试验可能会为 XLP 患者提供长期治疗选择。我们寻求资金来生成和测试适合临床使用的病毒，并在大奥蒙德街医院招募 7 名患者进行临床试验。我们计划纳入 1 岁以上且 18 岁以下确诊为 XLP 的患者。 T 细胞将被收集、校正和冷冻，以确保我们有足够的基因校正细胞回馈给患者。将对患者进行监测，以确定治疗的安全性和有效性，重点是基因校正细胞的检测以及在没有感染风险的情况下停止免疫球蛋白治疗的能力。这将是 XLP 的首次此类试验，概述的 T 细胞基因治疗方法可用于治疗影响 T 细胞的其他免疫疾病。我们在针对免疫性疾病进行成功的基因治疗试验方面拥有丰富的经验，如果我们能够证明这种治疗有效，我们将进行一项关键的注册试验，从而获得许可，从而使这种疗法得到更广泛的应用。