Memory T cells to improve immunity after TCRab/CD19 depleted haploidentical donor stem cell transplantation for inborn errors of immunity

我们计划研究一种名为CD45RO+Memory T细胞Addback的细胞疗法在患有先天性免疫缺陷(IEI)的儿童中进行造血干细胞移植后的益处。IEI与严重情况下儿童早期生活质量下降和死亡风险相关。干细胞移植是治疗受影响患者的一种公认的治疗方法，但约25%-60%的合格患者缺乏合适的组织类型匹配的捐赠者。另一种选择是使用不匹配的家庭或不相关的捐赠者，例如父母，但这有一个问题。干细胞收获不仅包括将继续重新填充患者骨髓的干细胞，还包括具有武装并具有潜在危险的成熟免疫细胞的混合物。这些细胞包括一组白细胞(好的T细胞)，它们对抵抗感染非常有用。然而，在移植后，来自捐赠者的不良T细胞会攻击患者的正常细胞，导致一种称为移植物抗宿主病(GvHD)的疾病。T细胞对组织类型的差异非常敏感，因此移植物抗宿主病是不匹配移植的一大风险。出于这个原因，从移植物中移除大多数T细胞是标准做法，但在这种类型的移植后，免疫系统需要很长时间才能恢复。这会导致严重感染的高风险，甚至在移植期间死亡，直到免疫系统恢复。患有IEI的患者在接受移植时经常伴随着许多感染，这使他们在移植后面临特别大的风险。我们计划研究的新细胞疗法是一种方法，在T细胞耗尽的不相合移植后，将供者移植物中良好的T细胞(记忆T细胞，CD45RO+)作为“加背式”(或助推器)送回移植物。不良T细胞(幼稚T细胞，CD45RA+)首先被过滤掉，以将GvHD的风险降至最低。最近在接受白血病移植的儿童中进行的这种“回补”试验显示，这种“回补”的好处包括更快的免疫恢复、较低的感染率和提高存活率。我们计划在一项试验中测试T细胞回补，以确定它是否改善了患有严重联合免疫缺陷(SCID)以外的IEI儿童的不匹配移植后的结果。有资格接受移植但没有匹配捐赠者的40名这样的儿童将被招募到试验中。这是一项分两个阶段进行的研究：在第一阶段，将在4名移植患者身上测试每种剂量的3种不同剂量的addback；在第二阶段，将在另外26名患者身上测试最有希望的剂量。为了衡量T细胞回输的益处，我们将把这组患者与前几年接受不匹配移植但没有回补的50名患者，以及当代的40名患者进行比较，其中40名患者将接受匹配的供者移植，10名患者将接受不匹配的移植而没有回补。该项目将在纽卡斯尔大学、纽卡斯尔泰恩医院NHS基金会信托基金、大奥蒙德街儿童医院和莱登大学的合作项目纽卡斯尔和伦敦两个地点进行。这项研究将加深我们对记忆T细胞在接受干细胞移植的儿童中的作用的理解，并帮助开发一种安全有效的错配供者移植策略。这可能会对未来患有IEI的儿童如何进行移植产生重大影响。每个孩子都应该得到治疗，如果这项临床试验显示出有希望的结果，“没有合适的捐赠者”的主要障碍将被消除。鉴于我们是英国使用这种移植操作的最大的移植计划，以及我们在照顾患有IEI的儿童方面的广泛专业知识，我们处于进行这项试验的独特地位。

We plan to study the benefit of a cellular therapy called CD45RO+ memory T cell addback after haematopoietic stem cell transplantation from a mismatched donor in children with inborn errors of immunity (IEI).IEI are associated with reduced quality of life and risk of death in early childhood in severe cases. Stem cell transplantation is an established curative therapy for affected patients, but about 25-60% of those eligible lack a suitable tissue-type-matched donor. An alternative is to use a mismatched family or unrelated donor, such as a parent, but there is a catch. Stem cell harvests include not only the stem cells that will go on to repopulate the patient's bone marrow, but also a mixture of mature immune cells that are armed and potentially dangerous. These cells include a group of white blood cells (good T cells) which are very useful for fighting infections. However, after a transplant, bad T cells from the donor can attack normal cells in the patients and cause a condition called "graft-versus-host disease" (GvHD). T cells are very sensitive to tissue type differences, so GvHD is a big risk in mismatched transplants. For this reason, it is standard practice to remove most T cells from the graft, but it takes a long time for the immune system to recover after this type of transplant. This leads to a high risk of serious infections and even death during the transplant period, until the immune system recovers. Patients with IEI often go into transplant with many infections on board as part of their disease which makes them particularly at risk after transplant.The new cellular therapy we plan to study is a way of giving back the good T cells (memory T cells, CD45RO+) from a portion of the donor graft as an "addback" (or boost) after T cell-depleted mismatched transplant. The bad T cells (naïve T-cells, CD45RA+) are first filtered out to minimise any risk of GvHD. Recent trials of this "addback" in children having transplants for leukaemia show benefits including faster immune recovery, lower infection rate and improved survival.We plan to test T cell addback in a trial to see if it improves outcome after mismatched transplant in children with IEI other than severe combined immunodeficiency (SCID). Forty such children who are eligible for transplant but have no matched donor will be recruited to the trial. It is a two-stage study: in the first stage, 3 different doses of addback will be tested in 4 transplant patients for each dose; in the second stage, the most promising dose will be tested in 26 further patients. To measure the benefits of T cell addback, we will compare this group with 50 patients who received a mismatched transplant without addback in previous years, together with contemporary groups of 40 patients who will receive a matched donor transplant and 10 patients who will receive a mismatched transplant without addback. The project will be performed at two sites, Newcastle and London, as a collaborative project between Newcastle University, the Newcastle upon Tyne Hospitals NHS Foundation Trust, Great Ormond Street Hospital for Children and University of Leiden.This research will enhance our understanding of the role of memory T cells in children undergoing stem cell transplantation and help develop a safe and effective mismatched donor transplant strategy. It may have a major impact on how transplant is performed in children with IEI in the future. Every child deserves a cure and the major obstacle of "no suitably matched donor" will be eliminated if this clinical trial demonstrates promising outcomes. Given that we are the largest transplant programme using such graft manipulation in the UK and with our extensive expertise in caring for children with IEI, we are uniquely placed to perform this trial.