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连锁淋巴增生性疾病（XLP）是一种影响男孩的罕见遗传疾病。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）有危险的免疫反应，复发性感染，约三分之一的患者发展为淋巴瘤。受影响的男孩在童年或青春期早期患病。目前，患者经常接受终身免疫球蛋白治疗和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，但结果取决于有一个匹配良好的捐赠者，最好在并发症发生之前进行移植。多达50%的患有活动性疾病的患者从不匹配的供体移植后将无法存活。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，预防终身感染并降低恶性肿瘤和HLH的风险。在这种情况下看到的大多数免疫系统异常是由于T细胞功能异常而引起的。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细胞来纠正许多这些异常，包括免疫球蛋白产生，对免疫攻击的抗体反应和肿瘤形成。因此，我们认为，仅对患者的T细胞进行基因治疗将有助于缓解他们的许多症状，并且可能是比无关供体骨髓移植更安全的治疗选择。通过使用患者自身的细胞，我们避免了移植物抗宿主病的任何风险，这种疾病可能导致移植后的显著发病率和死亡率，并且我们能够使用比骨髓移植所涉及的更少的化疗。正如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）将缺陷基因的正常拷贝转移到患者T细胞中。目前还没有与这种类型的病毒或注入患者与基因修饰的T细胞（例如治疗特定形式的癌症）相关的安全性问题。该提案的目的是T细胞基因治疗的早期临床试验，可能为XLP患者提供长期治疗选择。我们寻求资金，以产生和测试适合临床使用的病毒，并在大奥蒙德街医院进行临床试验，招募7名患者。我们计划纳入1岁以上和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，重点是检测基因校正的细胞和停止免疫球蛋白治疗而无感染风险的能力。这将是XLP的第一次试验，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。我们在为免疫疾病提供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是有效的，我们将进行关键的注册试验，允许向许可证迈进，这将使这种治疗更广泛地提供。