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连锁的淋巴增生性疾病（XLP）是影响男孩的罕见遗传疾病。症状有所不同，但大多数患者对某些病毒感染（称为淋巴淋巴细胞增多症或HLH），复发性感染和大约三分之一的淋巴瘤具有危险的免疫反应。受影响的男孩在童年或青春期生病。目前，患者经常接受终身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，但结果取决于匹配良好的供体，最好是在并发症发生之前移植。从不匹配的供体移植的活性疾病患者中，多达50％的患者将无法在移植后生存。对于缺乏合适的移植供体的患者来说，明确的需求清楚，需要采取替代方法来减轻疾病并发症的负担，防止感染终生并降低恶性肿瘤和HLH的风险。由于T细胞的异常功能，在这种情况下看到的大多数免疫系统异常。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，我们可以纠正许多此类异常，包括免疫球蛋白的产生，对免疫攻击的抗体反应以及通过提供基因校正的T细胞的肿瘤形成。因此，我们认为，仅患者T细胞的基因治疗将有助于许多症状，并且可能比无关供体的骨髓移植更安全的治疗选择。通过使用患者自身的细胞，我们避免了任何患有移植物与宿主疾病的风险，这些风险可能会导致移植后出现明显的发病率和死亡率，并且与骨髓移植相比，我们能够使用更少的化学疗法。就像在我们部门正在进行的其他基因治疗临床试验中一样，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。与这种类型的病毒或将基因修饰的T细胞注入患者（例如，治疗特定形式的癌症）没有安全问题。该提案的目的是T细胞基因治疗的早期临床试验，可以为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进行招募7名患者的临床试验。我们计划包括1岁以上和18岁以下的患者，并确认XLP诊断。将收集，校正和冷冻T细胞，以确保我们有足够的基因校正细胞回馈患者。将监测患者，以建立针对检测基因校正细胞的治疗的安全性和功效，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的同类试验，T细胞基因治疗方法概述可用于治疗影响T细胞的其他免疫疾病。我们在提供成功的免疫疾病基因治疗试验方面拥有丰富的经验，如果我们可以证明这种治疗有效，我们将进行一项关键注册试验，从而允许迈向许可，这将使该治疗更广泛地使用。