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

x连锁淋巴细胞增生性疾病（XLP）是一种罕见的遗传性疾病，影响男孩。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）、复发性感染有危险的免疫反应，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发病。目前，患者通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一种治疗方法，但结果取决于有一个匹配良好的供体，最好是在并发症发生之前进行移植。从不匹配供体移植的活动性疾病患者中，高达50%的患者在移植后无法存活。对于缺乏合适移植供体的患者，显然存在未满足的需求，需要其他方法来减轻疾病并发症的负担，预防终身感染，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细胞功能异常引起的。我们已经通过使用XLP小鼠模型和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，包括免疫球蛋白的产生、对免疫挑战的抗体反应和肿瘤的形成。因此，我们认为，单独对患者的T细胞进行基因治疗将有助于缓解他们的许多症状，并且可能是一种比从无血缘关系的捐赠者那里进行骨髓移植更安全的治疗选择。通过使用患者自身的细胞，我们避免了任何移植物抗宿主病的风险，这种疾病在移植后会导致显著的发病率和死亡率，而且我们能够使用比骨髓移植更少的化疗。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的T细胞中。这种类型的病毒或给病人注入基因修饰的T细胞（例如治疗特定形式的癌症）没有安全问题。这项提议的目的是T细胞基因治疗的早期临床试验，这可能为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。我们计划纳入确诊为XLP的1岁以上和18岁以下的患者。T细胞将被收集、校正并冷冻，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细胞和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的首次同类试验，概述的T细胞基因治疗方法可用于治疗其他影响T细胞的免疫疾病。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，允许向许可迈进，这将使这种疗法更广泛地应用。

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.