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

TCRab/CD19 耗尽的单倍相合供体干细胞移植治疗先天性免疫缺陷后，记忆 T 细胞可提高免疫力

• 批准号: MR/W021587/1
• 负责人: Sophie Hambleton
• 金额: $ 248.94万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW021587%2F1
• 关键词: Memory; cells; improve; immunity; after

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.

我们计划研究一种名为 CD45RO+ 记忆 T 细胞加回的细胞疗法对患有先天性免疫缺陷 (IEI) 的儿童进行造血干细胞移植后的益处。IEI 严重时会导致儿童早期的生活质量下降和死亡风险。干细胞移植是一种针对受影响患者的既定治疗方法，但大约 25-60% 的合格患者缺乏合适的组织类型匹配的供体。另一种方法是使用不匹配的家庭或无关的捐赠者，例如父母，但有一个问题。干细胞收获不仅包括将继续重新填充患者骨髓的干细胞，还包括已武装且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 T 细胞），对于对抗感染非常有用。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，导致一种称为“移植物抗宿主病”(GvHD) 的疾病。 T 细胞对组织类型差异非常敏感，因此 GvHD 是不匹配移植的一大风险。因此，从移植物中去除大部分 T 细胞是标准做法，但此类移植后免疫系统需要很长时间才能恢复。这导致移植期间严重感染甚至死亡的高风险，直到免疫系统恢复。 IEI 患者在接受移植时通常会出现许多感染，这是其疾病的一部分，这使得他们在移植后面临特别高的风险。我们计划研究的新细胞疗法是一种从供体移植物的一部分中回馈良好 T 细胞（记忆 T 细胞，CD45RO+）的方法，作为 T 细胞耗尽的不匹配移植后的“回加”（或增强）。不良 T 细胞（初始 T 细胞，CD45RA+）首先被滤除，以尽量减少 GvHD 的风险。最近在接受白血病移植的儿童中进行的这种“回加”试验显示出好处，包括更快的免疫恢复、降低感染率和提高生存率。我们计划在一项试验中测试 T 细胞回加，看看它是否可以改善除严重联合免疫缺陷 (SCID) 之外的 IEI 儿童错配移植后的结果。四十名符合移植资格但没有匹配捐赠者的儿童将被招募参加试验。这是一个两阶段的研究：第一阶段，将在4名移植患者中测试3种不同剂量的addback，每种剂量；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 细胞回加的益处，我们将该组与前几年接受不带回加的错配移植的 50 名患者进行比较，同时将接受匹配供体移植的 40 名患者和 10 名接受不带回加的错配移植的患者组成的当代组进行比较。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、泰恩河畔纽卡斯尔医院 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，并帮助制定安全有效的错配供体移植策略。它可能会对未来如何对 IEI 儿童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，“没有合适的匹配捐赠者”的主要障碍将被消除。鉴于我们是英国最大的使用此类移植物操作的移植项目，并且凭借我们在护理 IEI 儿童方面的丰富专业知识，我们在开展这项试验方面拥有得天独厚的条件。