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Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1

Salima Hacein-Bey-Abina1, Alexandrine Garrigue, Gary P Wang

  • 1Department of Biotherapy, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université René Descartes, Paris, France. salima.hacein-bey@nck.ap-hop-paris.fr

The Journal of Clinical Investigation
|August 9, 2008
PubMed

Insights

Gene therapy for severe combined immunodeficiency (SCID-X1) successfully treated patients but led to T cell leukemia due to vector insertions near proto-oncogenes. Chemotherapy achieved remission in most cases, restoring immune function.

Area of Science:

  • Immunology
  • Oncology
  • Gene Therapy

Background:

  • X-linked severe combined immunodeficiency (SCID-X1) is a genetic disorder affecting T cell development.
  • Gene therapy using gammaretroviral vectors to correct the IL2RG gene in CD34+ cells was previously successful in treating SCID-X1.
  • A subset of treated patients developed T cell leukemia months after gene therapy.

Purpose of the Study:

  • To investigate the genetic mechanisms underlying T cell leukemia development post-gene therapy for SCID-X1.
  • To analyze the specific vector integration sites and additional genetic abnormalities in leukemic cells.
  • To evaluate the efficacy of chemotherapy in treating therapy-induced leukemia.

Main Methods:

  • Analysis of vector insertion sites in leukemic cells from patients with SCID-X1 gene therapy-induced leukemia.
  • Comprehensive genetic profiling of blast cells, including chromosomal analysis and mutation detection.
  • Assessment of patient response to chemotherapy and immune reconstitution.

Main Results:

  • Vector insertions near proto-oncogenes LMO2, BMI1, and CCND2 were identified in leukemic cells.
  • Additional genetic abnormalities, including NOTCH1 mutations and CDKN2A deletions, were found.
  • Chemotherapy induced sustained remission in 3 of 4 patients, associated with polyclonal T cell recovery.

Conclusions:

  • Gammaretroviral vector integration near specific proto-oncogenes can contribute to T cell leukemia development in SCID-X1 gene therapy.
  • A complex genetic network involving multiple abnormalities drives leukemogenesis in these patients.
  • Chemotherapy can be effective in managing gene therapy-induced leukemia, allowing continued benefit from gene transfer.

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