Efficacy of gene therapy for X-linked severe combined immunodeficiency

Abstract

Background: The outcomes of gene therapy to correct congenital immunodeficiencies are unknown. We reviewed long-term outcomes after gene therapy in nine patients with X-linked severe combined immunodeficiency (SCID-X1), which is characterized by the absence of the cytokine receptor common gamma chain.

Methods: The nine patients, who lacked an HLA-identical donor, underwent ex vivo retrovirus-mediated transfer of gamma chain to autologous CD34+ bone marrow cells between 1999 and 2002. We assessed clinical events and immune function on long-term follow-up.

Results: Eight patients were alive after a median follow-up period of 9 years (range, 8 to 11). Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients. However, acute leukemia developed in four patients, and one died. Transduced T cells were detected for up to 10.7 years after gene therapy. Seven patients, including the three survivors of leukemia, had sustained immune reconstitution; three patients required immunoglobulin-replacement therapy. Sustained thymopoiesis was established by the persistent presence of naive T cells, even after chemotherapy in three patients. The T-cell-receptor repertoire was diverse in all patients. Transduced B cells were not detected. Correction of the immunodeficiency improved the patients' health.

Conclusions: After nearly 10 years of follow-up, gene therapy was shown to have corrected the immunodeficiency associated with SCID-X1. Gene therapy may be an option for patients who do not have an HLA-identical donor for hematopoietic stem-cell transplantation and for whom the risks are deemed acceptable. This treatment is associated with a risk of acute leukemia. (Funded by INSERM and others.)

Figure 1. Vector Copy Numbers and T-Cell Subgroups after Gene Therapy

Patients were categorized into two groups: those in whom severe adverse events did not develop (Patients 1, 2, 6, and 8; left side of each panel) and those in whom severe adverse events did develop (Patients 4, 5, 7, and 10; right side of each panel). Panel A shows the vector copy number in peripheral-blood mononuclear cells over time. In Patient 10, blast cells contained two copies, as previously reported. Panel B shows short-term and Panel C shows long-term T-cell reconstitution as evidenced by absolute CD3+ lymphocyte counts in whole blood, measured with the use of flow cytometry. Panel D shows the change over time in absolute numbers of CD4+ T cells, and Panel E shows the change over time in absolute numbers of CD45RA+CD4+–naive T lymphocytes in whole blood, as measured with the use of flow cytometry. Panel F shows the change over time in the number of T-cell–receptor excision circles (TRECs) in peripheral-blood mononuclear cells (PBMCs). Panel G shows the change over time in the absolute numbers of CD3+CD8+ T cells in whole blood, as measured with the use of flow cytometry. In Panels B, C, D, E, F, and G, the shaded areas indicate reference values for age-matched controls. In Panels A, C, D, E, F, and G, the arrows indicate the occurrence of leukemia and the duration of chemotherapy.

Figure 2. Serum Immunoglobulin Levels and Memory B-Cell Counts after Gene Therapy

The changes over time in levels of serum IgG (Panel A), IgA (Panel B), and IgM (Panel C) in Patients 1, 2, 6, and 8 (left side of each panel) and Patients 4, 5, 7, and 10 (right side of each panel) are shown. Data on IgG levels in Patients 6, 7, and 10 (who received immunoglobulin-replacement therapy) are not shown. Panel D shows the change over time in the proportion of CD19+CD27+ memory B cells as measured with the use of flow cytometry in Patients 1, 2, 6, 7, and 8. In all panels, arrows indicate the occurrence of leukemia and the duration of chemotherapy. The shaded areas indicate reference values for age-matched controls.