Treatment of young children with adenosine deaminase (ADA) deficiency (ADA-SCID) with an investigational ex vivo lentiviral hematopoietic stem and progenitor cell (HSPC) gene therapy proved effective and safe, and improved survival, according to studies conducted in both the U.S. and U.K. Results were published in The New England Journal of Medicine.
“Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is an inborn error of metabolism that results in the accumulation of adenosine and deoxyadenosine, inhibition of DNA synthesis and repair, and substantial abnormalities of thymocyte development. Patients with ADA-SCID have profound lymphocytopenia, impaired immune function, and failure to thrive and without treatment, die from infections by the age of two years,” noted Donald. B. Kohn, MD, of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles (UCLA), and colleagues.
Recommended treatment for ADA-SCID consists of enzyme-replacement therapy with pegylated ADA (PEG-ADA), but because long-term treatment does not give full immune reconstitution, allogeneic or autologous hematopoietic stem-cell gene therapy (HSCT) are recommended.
In 2016, an alternative treatment for these patients was approved in Europe—ex vivo autologous HSCT with a γ-retroviral vector—but it proved to have the potential to bring about resultant insertional oncogenesis, which in turn caused vector-related leukemia and myelodysplastic events.
In search of an alternative, Kohn and fellow researchers developed a self-inactivating lentiviral vector, EFS-ADA LV, in which they deleted the long-terminal-repeat enhancer-promoter and inserted an internal “shortened” human elongation factor 1α gene promotor, with less transactivation potential compared with γ-retroviral promoters, they noted.
To evaluate the safety and efficacy of this investigational treatment, they conducted a series of studies in the U.S. and U.K. In all, they included 50 children ages 1 month or older who had ADA-SCID but did not have an HLA-matched sibling or related donor. Most children were girls of White race between 10 and almost 12 months of age. All were receiving enzyme-replacement therapy at time of treatment and prophylactic antimicrobials at screening.
These children were treated with the investigational gene therapy, which was comprised of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that were transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA.
“In the U.S. studies, CD34+ HSPCs from bone marrow were enriched for transduction with EFS-ADA LV. In the U.K. study, CD34+ HSPCs were obtained from patients either by bone marrow harvest (three patients) or with the use of mobilized peripheral blood (17 patients). The minimum target yield was at least 1×106 CD34+ cells per kilogram of body weight (in the U.S. study in which a fresh formulation was used), 2×106 CD34+ cells per kilogram (in the U.S. study in which a cryopreserved formulation was used), and 4×106 CD34+ cells per kilogram (in the U.K. study),” explained Kohn et al.
They analyzed 24-month data from two U.S. studies using fresh and cryopreserved formulations, as well as 36-month data from a U.K. study in which children were treated with a fresh formulation. Overall survival was 100%, and event-free survival at 12 months 97% in the U.S. studies and 100% in the U.K. study. At 24 months, event-free survival was 97% and 95% respectively, and at 36 months in the U.K. study, 95%. Persistent engraftment of the genetically modified HSPCs was seen in 29 of 30 patients in the U.S. studies, and in 19 of 20 patients in the U.K. study.
Sustained metabolic detoxification and ADA activity level normalization were demonstrated by all patients. A full 90% of U.S. children who discontinued immunoglobulin-replacement therapy by 24 months demonstrated robust immune reconstitution, as did 100% of those in the U.K study at 36 months.
“Autologous CD34+ HSPCs were successfully transduced with EFS-ADA LV for all patients. After infusion, sustained levels of gene marking in leukocytes, including short-lived granulocytes, were present, a finding that suggests successful and stable engraftment of genetically modified long-term repopulating HSPCs,” noted Kohn and colleagues.
Safety end-points included the incidence/grade of adverse events and serious adverse events, including detection of replication-competent lentivirus or clonal expansion.
Kohn et al observed no monoclonal expansion, leukoproliferative complications, replication-competent lentivirus emergence, autoimmunity, or graft-versus-host disease. All patients reported adverse events, the majority of which were mild or moderate and considered conditioning-treatment related.
In the U.S. studies, 12 patients had one or more serious adverse events, most commonly infection (27%) and gastrointestinal events (17%). Only one of these events (staphylococcal bacteremia caused by fresh product contamination) was considered treatment-related. In the U.K. study, 25 patients had serious adverse events, with pyrexia (30%) being the most common. Like the U.S. study, one treatment-related serious adverse event occurred (staphylococcal infection) and was also due to drug-product contamination.
“The absence of graft-versus-host disease and the obviation of immunosuppressive therapies are major potential advantages of autologous HSPC gene therapy. None of the patients described here had evidence of replication-competent lentivirus or clonal expansions, which adds to the growing evidence for the safety of lentiviral vectors that has been seen in other clinical studies…” they noted.
“Other potential advantages of gene therapy over allogeneic HSCT include the absence of a donor requirement and lower toxicity, since less conditioning is required. Furthermore, as compared with HSCT, in which enzyme-replacement therapy is discontinued before treatment in order to limit the expansion of host T cells and the potential for graft-versus-host disease, a gene-therapy approach allows for continuation of enzyme-replacement therapy during immune reconstitution and thus for continued protection against infections during this period,” concluded Kohn and fellow researchers.
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U.S. and U.K. researchers reported 100% overall survival at 12 months, and 100% at 24 months for patients in all three studies; in the single U.K. study, overall survival was still 100% at 36 months.
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Across all patients in the three studies, no events of monoclonal expansion, leukoproliferative complications, emergence of replication-competent lentivirus, or deaths were seen.
Liz Meszaros, Deputy Managing Editor, BreakingMED™
This study was supported by grants from the National Institutes of Health (NIH_), the National Human Genome Research Institute intramural program, the National Institute of Allergy and Infectious Diseases (NIAID) intramural program, the National Gene Vector Biorepository, the California Institute for Regenerative Medicine, the Medical Research Council, the National Institute for Health Research Biomedical Research Center at the Great Ormond Street Hospital for Children NHS Foundation Trust and University College London, and Orchard Therapeutics.
Kohn received consultant fees from Allogen Therapeutics and Orchard Therapeutics. He is senior inventor on UC Regents IP for lentiviral vector for ADA SCID licensed to Orchard Therapeutics.
Cat ID: 497
Topic ID: 495,497,497,730,187,138,192,925
