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

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.