Adoptive T cell immunotherapy therapy for adenovirus infection in transplant patients

骨髓移植用于治疗白血病，涉及将血液或骨髓从捐赠者转移到患者身上。不幸的是，患者必须进行免疫抑制，以确保移植物不被排斥，这使得通常只会导致轻微症状的病毒成为对健康的主要威胁。有一些抗病毒药物可用于治疗其中一些病毒(如爱泼斯坦-巴尔病毒或巨细胞病毒)，但对腺病毒，没有有效和批准的治疗方法。腺病毒通常会在幼儿中引起轻微的呼吸道感染，大多数人在青春期时至少感染过一种腺病毒。因此，我们通常对同一种病毒株的进一步感染具有持久的免疫力。我们知道，在移植环境中，如果对病毒的免疫反应能够恢复，患者很有可能控制感染。做到这一点的一种方法是使用来自移植捐赠者的白细胞(T)，只选择那些能够识别病毒的细胞，从而停止感染周期。这项提议旨在通过将供者的腺病毒特异性T细胞与一种模仿它们通常识别的病毒部分的分子结合起来，来选择腺病毒特异的T细胞。这种分子本身被标记在一个微小的磁性颗粒上，这样所需的细胞就可以从其他细胞中分离出来，并移植到骨髓接受者体内。这项工作在捐赠者对病毒有很大免疫反应的情况下被证明是安全和有效的，但现在我们希望在更具挑战性的情况下发展它，在这种情况下免疫反应的水平要低得多。这项研究将作为早期临床试验进行，旨在确定该方法的可行性，但也将有将腺病毒感染降至最低的次要目标。

Bone marrow transplantation is used to treat leukaemia and involves the transfer of blood or bone marrow from a donor to the patient. Unfortunately patients have to be immunosuppressed to ensure that the graft is not rejected and this allows viruses that normally cause only mild symptoms to become a major threat to health. There are antiviral drugs available to treat some of these viruses (eg Epstein Barr Virus or cytomegalovirus) but for adenovirus there is no effective and approved treatment. Adenovirus normally causes mild respiratory infections in young children and most people have had at least one adenovirus infection by adolescence. As such we normally have a long lasting immunity to further infections with the same virus strain. We know that in the transplant setting, if the immune response to the virus can be restored, the patient has a good chance of controlling the infection. One way to do this is to use white (T) cells from the transplant donor, selecting just those cells that can recognise the virus, thereby halting the infectious cycle. This proposal aims to select adenovirus-specific T cells from the donor by binding them to a molecule that mimics the part of the virus that they would normally recognise. This molecule is itself tagged to a microscopic magnetic particle so that the required cells can be separated from other cells and transplanted into the bone marrow recipient. This work has proven safe and effective in situations in which the donor has a large immune response to the virus but now we wish to develop it in a more challenging situation in which the level of the immune response is much smaller. The research will be conducted as an early phase clinical trial which aims to establish the feasibility of the method but will also have the secondary objective of minimising the adenovirus infection.