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

我们计划研究一种称为CD45RO+记忆T细胞补充的细胞疗法对先天性免疫缺陷（IEI）儿童的益处，这种疗法是在来自不匹配供体的造血干细胞移植后进行的。在严重的情况下，儿童早期的生活质量下降和死亡风险与精神创伤有关。干细胞移植是一种公认的治疗受影响患者的治疗方法，但约有25-60%的患者缺乏合适的组织类型匹配的供体。另一种选择是使用不匹配的家庭或不相关的捐赠者，如父母，但有一个陷阱。干细胞收获不仅包括将继续重新填充患者骨髓的干细胞，还包括成熟免疫细胞的混合物，这些细胞是武装的，具有潜在的危险。这些细胞包括一组白细胞（好的T细胞），它们对对抗感染非常有用。然而，移植后，来自供体的不良T细胞会攻击患者体内的正常细胞，导致一种叫做“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，因此在不匹配的移植中，GvHD的风险很大。因此，标准做法是从移植物中去除大部分T细胞，但这种类型的移植后免疫系统需要很长时间才能恢复。这导致在移植期间严重感染甚至死亡的高风险，直到免疫系统恢复。患有IEI的患者在接受移植手术时通常会有许多感染，这是他们疾病的一部分，这使得他们在移植后特别危险。我们计划研究的新细胞疗法是在T细胞耗尽的错配移植后，将一部分供体移植物中的好T细胞（记忆T细胞，CD45RO+）作为“补充”（或增强）。坏的T细胞（naïve T细胞，CD45RA+）首先被过滤掉，以尽量减少GvHD的风险。最近在接受白血病移植手术的儿童中进行的这种“补充”试验显示，其益处包括更快的免疫恢复、更低的感染率和更高的生存率。我们计划在一项试验中测试T细胞补充，看看它是否能改善除严重联合免疫缺陷（SCID）以外的IEI儿童错配移植后的预后。40名符合移植条件但没有匹配供体的儿童将被招募参加试验。这是一项两阶段的研究：第一阶段，将在4名移植患者中测试3种不同剂量的addback；在第二阶段，最有希望的剂量将在另外26名患者中进行测试。为了衡量T细胞补充的益处，我们将把这一组与前几年接受无补充的错配移植的50名患者进行比较，同时将40名接受匹配供体移植的患者和10名接受无补充的错配移植的患者进行比较。该项目将在纽卡斯尔和伦敦两个地点进行，作为纽卡斯尔大学、纽卡斯尔河畔泰恩医院NHS基金会信托基金、大奥蒙德街儿童医院和莱顿大学之间的合作项目。这项研究将增强我们对记忆T细胞在接受干细胞移植的儿童中的作用的理解，并有助于制定安全有效的错配供体移植策略。这可能会对将来如何在患有IEI的儿童中进行移植产生重大影响。每个孩子都应该得到治愈，如果这项临床试验显示出有希望的结果，“没有合适的匹配供体”的主要障碍将被消除。鉴于我们是英国使用这种移植物操作的最大移植项目，以及我们在照顾患有IEI的儿童方面的广泛专业知识，我们在进行这项试验方面处于独特的地位。

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.