Long-term Persistence of Polyclonal T Cell Repertoire in Gene Therapy for X-linked Severe Combined Immunodeficiency

Researchers in London, United Kingdom, have reported promising results in a study on gene therapy for X-linked severe combined immunodeficiency (SCID-X1). The condition is caused by mutations in the common cytokine receptor γ chain, leading to impaired T and natural killer cell function. Ten children with SCID-X1 were treated with autologous CD34(+) hematopoietic stem and progenitor cells transduced with a conventional gammaretroviral vector. The patients did not receive myelosuppressive conditioning, and their immunological recovery was monitored after cell infusion. The study found that all patients had a functional polyclonal T cell repertoire restored after a median follow-up of 80 months, with high survival rates for up to 9 years.

Key Takeaways:

• Ten children with SCID-X1 were treated with gene therapy using autologous CD34(+) hematopoietic stem and progenitor cells transduced with a conventional gammaretroviral vector.
• The patients did not receive myelosuppressive conditioning, and their immunological recovery was monitored after cell infusion.
• All patients had a functional polyclonal T cell repertoire restored after a median follow-up of 80 months (range, 54 to 107 months).
• Humoral immunity only partially recovered, but was sufficient in some patients to allow for withdrawal of immunoglobulin replacement.
• Three patients developed antibiotic-responsive acute pulmonary infection after discontinuation of antibiotic prophylaxis and/or immunoglobulin replacement.
• One patient developed acute T cell acute lymphoblastic leukemia due to up-regulated expression of the proto-oncogene LMO-2 from insertional mutagenesis, but maintained a polyclonal T cell repertoire through chemotherapy and entered remission.
• Gene therapy for SCID-X1 without myelosuppressive conditioning was associated with high survival rates for up to 9 years.
• Further studies are warranted to define the role of this treatment modality alongside conventional HSCT for SCID-X1.

Statistics:

• 10 children with SCID-X1 were treated with gene therapy.
• Median follow-up was 80 months (range, 54 to 107 months).
• All patients had a functional polyclonal T cell repertoire restored.
• Three patients developed antibiotic-responsive acute pulmonary infection.
• One patient developed acute T cell acute lymphoblastic leukemia.
• Gene therapy was associated with high survival rates for up to 9 years.

Sources:

• Gaspar, H.B., et al. "Long-term persistence of a polyclonal T cell repertoire after gene therapy for X-linked severe combined immunodeficiency." Science Translational Medicine, vol. 3, no. 97, 2011, pp. 97ra79.