Combined Immunodeficiencies
Conditions
Keywords
Combined immunodeficiencies, hematopoietic stem cell transplantation, CD45RA, primitive immunodeficiencies, pediatric transplantation, CD45RA depletion
Brief summary
The purpose of this study is to evaluate selective depletion of naïve CD45RA+ T cells from allogenic peripheral blood stem cell graft in children transplanted for combined immune deficiency. The aims of this procedure are to prevent graft versus host disease (GVHD) while preserving anti-infectious response from donor memory T lymphocytes.
Detailed description
Combined immunodeficiencies (CIDs) are an heterogeneous group of primitive immunodeficiency (PID), which affect T cells development, function or both. These inherited conditions can only be cured by allogeneic hematopoietic stem cell transplantation (HSCT). These procedures have a high risk of morbidity and mortality such a graft versus host disease (GVHD), rejection of the graft and serious infections, especially in this population of children with PID. GVHD is more frequent and severe if the donor is not an identical sibling and/or presents an HLA-mismatch. GVHD requires high immunosuppression as prevention and treatment, and therefore impedes immunity against infections. In vitro and animal models suggest that GVHD is mediated by naïve T cells. The aim of this study is to decrease the rate and severity of GVHD after selective depletion of naïve CD45RA+ T cells from allogeneic hematopoietic stem cell grafts in patients with CIDs with high risk of severe GVHD, and to preserve immunity against pathogens in a population with high vulnerability to infections. The project aims is, first, to show improvement of rejection-free and GVH-free survival 12 months post-transplant, and secondly, to show the decrease of viral infection, and assess immune reconstitution kinetic and quality and specific antiviral responses, after a engraftment with naïve cell depleted allograft.
Interventions
BIOLOGICALDepletion in CD45RA graft donor
Experimental treatment: negative fraction after CD34+ selection from PBSC graft is depleted of naïve CD45RA+ cells. this fraction is reinjected to the recipient and is the experimental product. Conditioning regimen: Up-front ATG from D-14 toD-11 Busulphan IV from D-8 to -5 Fludarabine from D-7 to D-4 Thiothepa D-3 to D-2 Graft: CD34+ cells positively selected cells from PBSC of the donor Post transplant immunosuppression: ciclosporin started at D-1 to D+100
Sponsors
Assistance Publique - Hôpitaux de Paris
URC-CIC Paris Descartes Necker Cochin
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
* Patient from 12 months to 18 years * Combined immunodeficiencies with known molecular diagnosis or if unknown, corresponding of p-CID study's definition * Hematopoietic stem cell Transplantation planned with one of the following donors : * sibling with 1 or 2 HLA antigens mismatch * parent 10/10 or 9/10 identical * unrelated donor: 10/10 or 9/10 identical * Consent form signed by the child's legal guardian * Patient using effectiveness contraception during this trial * Affiliated or beneficiary of a health insurance regimen
Exclusion criteria
* Wiskott-Aldrich syndrome * Ongoing pregnancy * Positive HIV PCR * Contraindication for hematopoetic stem cell transplantation * Geno-identical donor in the siblings * hematopoetic stem cell transplantation antecedent
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of death | 12 months after the transplantation |
| Number of graft rejection | 12 months after the transplantation |
| Number of graft versus host disease (GVHD) grade III or IV | 12 months after the transplantation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Need of antiviral treatment | 12 months after the transplantation | to assess viral infection |
| T Lymphocyte proliferations to phytohemagglutinin (PHA) | 12 months after the transplantation | to assess immune reconstitution |
| Proportion of T CD4 and CD8 lymphocytes specific of cytomegalovirus, Epstein Barr virus and adenovirus | 12 months after the transplantation | to assess specific antiviral response |
Countries
France
Contacts
STUDY_CHAIRMarina CAVAZZANA, MD, PhD
Assistance Publique Hopitaux de Paris
Outcome results
None listed