CMV TCR Gene Therapy: A Phase I/II Safety, Toxicity and Feasibility Study of Adoptive Immunotherapy in Allo-HSCT

CMV TCR 基因治疗：同种异体造血干细胞移植过继免疫治疗的 I/II 期安全性、毒性和可行性研究

• 批准号: G0701703/1
• 负责人: Emma Morris
• 金额: $ 38.13万
• 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: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0701703%2F1
• 关键词: CMV; TCR; Gene; Therapy; Phase

Patients with cancers of the blood and bone marrow are often given a form of treatment called a stem cell (or bone marrow) transplant. During the transplant procedure the patient will be given potent chemotherapy and/or radiotherapy to kill off residual cancer cells before the new stem cells are re-infused from the bone marrow donor, often a sibling. In order for the new stem cells to persist in the patient, powerful drugs need to be given to suppress the patient?s own immune system. The period of profound immune suppression can last for up to 6 months post transplant. During this time the reactivation of viruses, such as cytomegalovirus (CMV) is very common. CMV reactivation in immunosuppressed patients can lead to progressive infection and even death. In healthy individuals CMV rarely causes any problems as the T cells of the immune system are able to keep the virus in check. Individuals who have previously been infected with CMV (50% UK adults) have small numbers of T cells in their blood which can recognise and kill CMV-infected cells. Recently, researchers in the UK and Europe have shown that these CMV-specific T cells taken from bone marrow donors can be infused into the transplant patient and control CMV infection in the patient. Typically, a single infusion of the donor?s T cells is effective. This approach avoids the need for repeated anti-viral drugs, which have significant side effects and usually require the patient to be re-admitted to hospital for prolonged periods. However, many patients have transplant donors who have not been previously infected with CMV. These donors will not have any pre-made immune T cells which can recognise CMV. We propose to take the T cells of CMV negative donors and genetically modify them so that they are able to recognise and kill CMV-infected cells. This will be done by growing the donor T cells in the laboratory in the presence of a specially modified virus called a retroviral vector. This procedure will transfer a gene to the T cells, which allows them to recognize protein fragments (peptides) of the CMV virus called CMV pp65. The gene transferred to the T cells enables them to make a new T cell receptor (CMV TCR), which specifically recognises the CMV pp65 peptide. The CMV TCR gene-modified T cells will be infused into the patient if they reactivate CMV as part of this Phase I/II clinical trial.

患有血癌和骨髓癌的患者通常会接受一种称为干细胞（或骨髓）移植的治疗。在移植过程中，患者将接受强效化疗和/或放疗，以杀死残留的癌细胞，然后再将来自骨髓捐赠者（通常是兄弟姐妹）的新干细胞重新注入骨髓。为了让新的干细胞在病人体内持续存在，需要给病人强有力的药物来抑制这种情况吗？人体自身的免疫系统。深度免疫抑制期可在移植后持续长达6个月。在此期间，病毒的再激活，如巨细胞病毒（CMV）是非常常见的。免疫抑制患者的巨细胞病毒再激活可导致进行性感染甚至死亡。在健康个体中，巨细胞病毒很少引起任何问题，因为免疫系统的T细胞能够控制病毒。以前感染过巨细胞病毒的人（50%的英国成年人）血液中有少量的T细胞，可以识别和杀死巨细胞病毒感染的细胞。最近，英国和欧洲的研究人员已经证明，这些从骨髓供体中提取的CMV特异性T细胞可以注入移植患者体内，并控制患者的CMV感染。一般来说，一次输注供体？T细胞是有效的。这种方法避免了反复使用抗病毒药物的需要，这些药物有明显的副作用，通常需要患者再次住院较长时间。然而，许多患者的移植供体以前没有感染过巨细胞病毒。这些捐献者将没有任何能够识别巨细胞病毒的预制免疫T细胞。我们建议对巨细胞病毒阴性供者的T细胞进行基因修饰，使其能够识别和杀死巨细胞病毒感染的细胞。这将通过在实验室中一种被称为逆转录病毒载体的特殊修饰病毒的存在下培养供体T细胞来完成。这个过程将把一个基因转移到T细胞中，使它们能够识别CMV病毒的蛋白质片段（肽），称为CMV pp65。转移到T细胞中的基因使它们能够制造一种新的T细胞受体（CMV TCR），这种受体能够特异性地识别CMV pp65肽。作为I/II期临床试验的一部分，如果CMV TCR基因修饰的T细胞重新激活CMV，将被输注到患者体内。