Subject(s)
Adenoviridae Infections/immunology , Adenoviridae/immunology , Cytomegalovirus Infections/immunology , Cytomegalovirus/immunology , T-Lymphocytes/immunology , Adult , Child, Preschool , Female , Hematopoietic Stem Cell Transplantation/methods , Humans , Infant , Male , Middle Aged , Young AdultABSTRACT
During the last decade, gene therapy via ex vivo gene transfer into autologous hematopoietic stem cells has emerged as a convincing therapy for severe combined immunodeficiency caused by ILR2G mutation (SCID-X1) despite the occurrence of genotoxicity caused by the integration of first-generation retroviral vectors. However, the place of gene therapy among the therapeutic armamentarium remains to be defined. We retrospectively analyze and compare clinical outcomes and immune reconstitution in 13 consecutive SCID-X1 patients having undergone haploidentical hematopoietic stem cell transplantation (HSCT) and 14 SCID-X1 patients treated with gene therapy over the same period at a single center level: the Necker Children's Hospital (Paris, France). Our results show a clear advantage in terms of T-cell development of gene therapy over HSCT with a mismatched donor. Patients treated with gene therapy display a faster T-cell reconstitution and a better long-term thymic output. Interestingly, this advantage of gene therapy vs haploidentical HSCT seems to be independent of the existence of clinical graft-versus-host disease in the latter condition. If data of safety are confirmed over the long term, gene therapy for SCID-X1 appears to be an equal, if not superior, alternative to haploidentical HSCT.
Subject(s)
Genetic Therapy , Hematopoietic Stem Cell Transplantation , Interleukin Receptor Common gamma Subunit/immunology , T-Lymphocytes/immunology , Thymus Gland/immunology , X-Linked Combined Immunodeficiency Diseases/therapy , Adolescent , Allografts , Child , Child, Preschool , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/genetics , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Humans , Infant , Interleukin Receptor Common gamma Subunit/genetics , Male , Mutation , Prospective Studies , Retrospective Studies , T-Lymphocytes/pathology , Thymus Gland/pathology , X-Linked Combined Immunodeficiency Diseases/genetics , X-Linked Combined Immunodeficiency Diseases/immunology , X-Linked Combined Immunodeficiency Diseases/pathologyABSTRACT
BACKGROUND: Combined immunodeficiencies (CIDs) form a heterogeneous group of inherited conditions that affect the development, function, or both of T cells. The treatment of CIDs with allogeneic hematopoietic stem cell transplantation (HSCT) is complicated by a high incidence of life-threatening infections and an increased risk of graft-versus-host disease (GVHD). OBJECTIVE: In view of the growing evidence that alloreactivity is mainly derived from human naive T cells, the selective depletion of naive T cells from allografts might constitute a way of reducing alloreactivity while maintaining memory T-cell responsiveness to pathogens. METHODS: Five consecutive patients with CIDs and chronic viral infections underwent an allogeneic, HLA-mismatched HSCT. Given the patients' infection status and the potential risk of severe GVHD in the mismatched setting, the CD34(-) fraction of the allograft was depleted of naive T cells by using magnetic CD45RA beads. RESULTS: Engraftment occurred in 4 of the 5 patients. No severe GVHD occurred. In the 4 engrafted patients viral infections were cleared within 2 months of the HSCT, and both cellular and humoral immunity were re-established within a year of the HSCT. An early T-cell response against viral pathogens was documented in 2 patients. CONCLUSION: The present pilot study shows that clinical-grade depletion of naive T cells from an allograft through the use of magnetic CD45RA beads seems to be a feasible and efficacious option for the treatment of patients with CIDs at high risk of GVHD, infection, or both in an HLA-mismatched setting.