Memory T cells to improve immunity after TCRαβ/CD19 depleted haploidentical donor stem cell transplantation for inborn errors of immunity
Non-severe combined immunodeficiency inborn errors of immunity
There are three arms across two sites with this trial; the intervention arm, control group 1 and control group 2. The interventional cohort (n=40) will include only children who are receiving a TCRαβ-HaploSCT (because of the lack of a suitable fully matched donor, either related or unrelated). They will be recruited in two stages; • Stage 1 will determine the optimum safe and effective dose of CD45RO+ memory T-cell addback. • Stage 2 will determine whether CD45RO+ memory T-cell addback can accelerate immune reconstitution and reduce the incidence, duration and severity of viral infection after TCRαβ-HaploSCT. Twelve participants at a single site (NUTH) will be randomised using Sealed Envelope and receive one of three different doses of CD45RO+ memory T-cell addback; 0.3 x 10^6/kg, 0.6 x 10^6/kg and 1.0 x 10^6/kg. Where a participant has been randomised but does not go on to receive the addback, for any reason, they will be withdrawn and an additional patient will be recruited. The next participant to reach the point of randomisation will automatically be allocated the same dose as the replaced participant and will effectively replace the participant who did not receive the addback. Randomisation should take place on Day -7 after baseline data collection is completed and when the conditioning regimen is commenced, however, if for any reason this is not possible then randomisation should occur as soon as possible and no later than the day of SCT (day 0). The addback will, in general, be administered on day 7 after TCRαβ-HaploSCT (day 0), but exceptionally its administration might be delayed by up to 2 days. If a participant does not receive addback within this window of 7 to 9 days post-transplant, an additional participant will be recruited to ensure data is available for twelve participants. An interim analysis will be performed after the first 12 participants complete three months' follow-up to determine the optimum dose of CD45RO+ memory T-cell addback to be
1. Age at least 1 month and up to 18 years at the time of scheduled transplant 2. Patients deemed clinically eligible for allogeneic HSCT for non-SCID IEI 3. No suitable conventional matched family donor#. 4. Patient has an eligible donor identified by the clinical transplant team: 4.1. Planned mismatched family or mismatched unrelated donor for TCRαβ-HaploSCT (Intervention and control group 1)* OR 4.2. 10/10 HLA-matched unrelated donor for MUD HSCT (control group 2) 5. Capacity for patient or the patient’s parent or guardian to provide written informed consent 1. # Donor choice is independent of this study and will be decided by the clinical team according to best clinical practice. Generally the hierarchy of preferred donor is 10/10 matched family donor > 10/10 matched unrelated donor > mismatched family donor > mismatched unrelated donor. However, depending on the specific disorder, a family member might not be a suitable donor if they are a carrier of the genetic disease, or the underlying molecular defect is unknown.
1. Lansky/Karnofsky performance score <30% 2. Ongoing active acute GvHD or chronic extensive GvHD due to previous allograft at the time of screening 3. Patient receiving an immunosuppressive treatment for GvHD due to previous allograft at time of screening 4. Presence of a medical condition indicating that survival will be dismal such as the requirement for a high setting of mechanical ventilation and severe failure of a major organ system 5. Pregnancy or breastfeeding in female patients Additional exclusion criteria for intervention group and control group 1 only (TCRαβ-HaploSCT) 1. Patients with donor-specific antibodies (DSA) against the potential stem cell donor using the standard test according to the institutional guideline