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Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency. 2021
Donald B Kohn, and
Claire Booth, and
Kit L Shaw, and
Jinhua Xu-Bayford, and
Elizabeth Garabedian, and
Valentina Trevisan, and
Denise A Carbonaro-Sarracino, and
Kajal Soni, and
Dayna Terrazas, and
Katie Snell, and
Alan Ikeda, and
Diego Leon-Rico, and
Theodore B Moore, and
Karen F Buckland, and
Ami J Shah, and
Kimberly C Gilmour, and
Satiro De Oliveira, and
Christine Rivat, and
Gay M Crooks, and
Natalia Izotova, and
John Tse, and
Stuart Adams, and
Sally Shupien, and
Hilory Ricketts, and
Alejandra Davila, and
Chilenwa Uzowuru, and
Amalia Icreverzi, and
Provaboti Barman, and
Beatriz Campo Fernandez, and
Roger P Hollis, and
Maritess Coronel, and
Allen Yu, and
Krista M Chun, and
Christian E Casas, and
Ruixue Zhang, and
Serena Arduini, and
Frances Lynn, and
Mahesh Kudari, and
Andrea Spezzi, and
Marco Zahn, and
Rene Heimke, and
Ivan Labik, and
Roberta Parrott, and
Rebecca H Buckley, and
Lilith Reeves, and
Kenneth Cornetta, and
Robert Sokolic, and
Michael Hershfield, and
Manfred Schmidt, and
Fabio Candotti, and
Harry L Malech, and
Adrian J Thrasher, and
H Bobby Gaspar
From the Departments of Microbiology, Immunology, and Molecular Genetics (D.B.K., K.L.S., D.A.C.-S., D.T., A.D., A. Icreverzi, P.B., B.C.F., R.P.H., M.C., A.Y., K.M.C., C.E.C., R.Z.), Pediatrics (D.B.K., T.B.M., S.D.O., S.S.), and Pathology and Laboratory Medicine (G.M.C.) and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (D.B.K., G.M.C.), University of California, Los Angeles (UCLA), and the Department of Pharmaceutical Services, Ronald Reagan UCLA Medical Center (J.T.), Los Angeles, and Stanford School of Medicine, Palo Alto (A.J.S.) - all in California; University College London Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust (C.B., J.X.-B., V.T., K. Soni, K. Snell, D.L.-R., K.F.B., K.C.G., C.R., N.I., S.A., H.R., C.U., A.J.T., H.B.G.), and Orchard Therapeutics (Europe) (D.A.C.-S., S.A., F.L., M.K., A.S., H.B.G.) - all in London; the National Institute of Allergy and Infectious Diseases (H.L.M.) and the National Human Genome Research Institute (E.G., R.S., F.C.), National Institutes of Health, Bethesda, MD; Cure 4 The Kids Foundation, Las Vegas (A. Ikeda); Cincinnati Children's Hospital Medical Center, Cincinnati (L.R.); Indiana University School of Medicine, Indianapolis (K.C.); Duke University, Durham, NC (R.P., R.H.B., M.H.); Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland (F.C.); and GeneWerk (M.Z., R.H., I.L., M.S.) and the German Cancer Research Center and the National Center for Tumor Diseases (M.Z., M.S.) - all in Heidelberg, Germany.
Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up. Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade. Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.).
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Blood,
