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.

我们计划研究一种称为CD45RO+记忆T细胞倒数的细胞疗法在造血干细胞从不匹配的供体中移植的造血干细胞移植后，患有先天性免疫误差（IEI）的儿童（IEI）.IEI。干细胞移植是针对患者的已建立的治疗疗法，但约有25-60％的合格患者缺乏合适的组织型匹配供​​体。另一种选择是使用不匹配的家庭或无关的捐助者（例如父母），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，还包括武装且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（良好的T细胞），这些细胞对于对抗感染非常有用。但是，在移植后，来自供体的不良T细胞会在患者中攻击正常细胞，并引起称为“移植物抗宿主病”的疾病（GVHD）。 T细胞对组织类型的差异非常敏感，因此GVHD是不匹配移植不匹配的很大风险。因此，从移植物中删除大多数T细胞是标准做法，但是在这种类型的移植后，免疫系统需要很长时间才能恢复。这会导致在移植期间发生严重感染甚至死亡的高风险，直到免疫系统恢复为止。 IEI患者通常会在移植中进行许多感染作为其疾病的一部分，这使得他们在移植后特别面临风险。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的T细胞（记忆T细胞，CD45RO+），作为“附加额”（或增强T细胞），后者（或增强）在depepeped thepeppect theepeppect thepback'（或增强）。首先要过滤不良的T细胞（幼稚的T细胞，CD45RA+），以最大程度地降低GVHD的任何风险。对患有白血病移植的儿童的这种“倒数”的最新试验表明，包括免疫恢复速度，较低的感染率和提高的生存率，我们计划在试验中测试T细胞倒数型，以查看其在其他IEI以外的IEI儿童中是否改善了其他IEI以外的其他严重合并免疫缺陷率（SCID）。有资格进行移植但没有匹配的捐助者的四十个这样的孩子将被招募到审判中。这是一项两阶段的研究：在第一阶段，每种剂量将在4例移植患者中测试3剂不同剂量的倒数剂。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细胞倒数额的好处，我们将与50例接受不匹配的移植的患者进行比较，这些患者在往年没有倒数额，以及40例患者的当代组，他们将接受匹配的供体移植和10名患者，他们将接受不匹配的移植不匹配而无需附加的移植。 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 tr​​ansplantation and help develop a safe and effective mismatched donor transplant strategy.这可能会对未来IEI儿童进行移植的方式产生重大影响。如果该临床试验表现出有希望的结果，则每个孩子都应得到治愈，而“无匹配的捐助者”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移植计划，并且在我们为IEI儿童带来的广泛专业知识的情况下，我们非常适合执行此试验。