Adoptive T cell immunotherapy therapy for adenovirus infection in transplant patients

骨髓移植用于治疗白血病，包括将血液或骨髓从捐赠者转移到患者身上。不幸的是，为了确保移植物不被排斥，患者必须进行免疫抑制，这使得通常只引起轻微症状的病毒成为对健康的重大威胁。有抗病毒药物可用于治疗这些病毒中的一些（如爱泼斯坦巴尔病毒或巨细胞病毒），但对于腺病毒，没有有效和批准的治疗方法。腺病毒通常在幼儿中引起轻微的呼吸道感染，大多数人在青春期至少感染过一次腺病毒。因此，我们通常对同一病毒株的进一步感染具有持久的免疫力。我们知道，在移植手术中，如果能恢复对病毒的免疫反应，病人就有很好的机会控制感染。一种方法是使用来自移植供体的白(T)细胞，只选择那些能够识别病毒的细胞，从而停止感染周期。这项提议的目的是通过将腺病毒特异性T细胞与一种分子结合，从而从供体中选择腺病毒特异性T细胞，这种分子可以模拟腺病毒正常识别的部分。这种分子本身被标记在一个微小的磁性粒子上，这样所需的细胞就可以从其他细胞中分离出来，并移植到骨髓受体中。在供体对病毒有强烈免疫反应的情况下，这项工作已被证明是安全有效的，但现在我们希望在免疫反应水平小得多的更具挑战性的情况下开展这项工作。该研究将作为早期临床试验进行，旨在确定该方法的可行性，但也将有最小化腺病毒感染的次要目标。

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.