Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study

Abstract

Background Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC) gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy. MethodsWe did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP) expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462) and EudraCT (number 2009-017346-32). Findings Between April 20, 2010, and Feb 26, 2015, nine patients (all male) were enrolled of whom one was excluded after screening; the age range of the eight treated children was 1·1-12·4 years. At the time of the interim analysis (data cutoff April 29, 2016), median follow-up was 3•6 years (range 0•5-5•6). Overall survival was 100%. Engraftment of genetically corrected HSPCs was successful and sustained in all patients. The fraction of WASP-positive lymphocytes increased from a median of 3•9% (range 1·8-35·6) before gene therapy to 66•7% (55·7-98·6) at 12 months after gene therapy, whereas WASP-positive platelets increased from 19•1% (range 4·1-31·0) to 76•6% (53·1-98·4). Improvement of immune function was shown by normalisation of in-vitro T-cell function and successful discontinuation of immunoglobulin supplementation in seven patients with follow-up longer than 1 year, followed by positive antigen-specific response to vaccination. Severe infections fell from 2•38 (95% CI 1·44-3·72) per patient-year of observation (PYO) in the year before gene therapy to 0•31 (0·04-1·11) per PYO in the second yea...

Gene therapy for severe combined immunodeficiencies and beyond

“…IS analysis in T cells with a vector copy number ranging from 1 to 3 per cell revealed that the frequency at which ISs were found in proto-oncogenes (and notably in LMO2 ) was much reduced (Hacein-Bey-Abina et al, 2014). Interestingly, no cases of leukemia have occurred in clinical trials based on the use of SIN vectors (whether γRV or LV constructs to transduce ex vivo CD34 hematopoietic progenitors in different diseases), since the 44 patients with ≥4 yr of follow-up are all leukemia free (Cartier et al, 2009; Cavazzana-Calvo et al, 2010; Aiuti et al, 2013; Biffi et al, 2013; Hacein-Bey-Abina et al, 2014; Ferrua et al, 2019; Sessa et al, 2016; Hacein-Bey Abina et al, 2015). T cell reconstitution was achieved in all but two patients treated with the SIN γRV-IL2RG vector associated with a major clinical benefit.…”

“…The treatment appears to have effectively induced the differentiation of WASp-expressing leukocytes and platelets. This expression has translated into the high-quality reconstitution of immune functions, including T and B cell functions, and the control of infections, allergy, and autoimmunity (Aiuti et al, 2013; Hacein-Bey Abina et al, 2015; Ferrua et al, 2019). The level of WASp expression, however, did not usually reach that of wild-type cells.…”

In vivo dynamics of human hematopoietic stem cells: novel concepts and future directions

“…Nowadays, hematopoietic stem cell transplantation (HSCT) remains the main curative treatment of many hematological malignancies and for inherited genetic disorders, 1,2 together with HSPC-based GT. 3,4,[36][37][38][39][40][41] In this context, understanding the role of HSPC subpopulations after transplantation is of paramount importance for the improvement of clinical procedures aimed at establishing not only LT maintenance of the graft but also early recovery from cell aplasia.…”

Multiplexed Proteomic Analysis for Diagnosis and Screening of Five Primary Immunodeficiency Disorders From Dried Blood Spots

“…Once diagnosed and treated appropriately, patients can often lead relatively normal lives (4,5). Curative therapies are also possible, depending on the disorder, with hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy (ERT), or gene therapy (5)(6)(7)(8)(9)(10)(11). Almost ubiquitously, early detection of PIDDs is extremely important in controlling and preventing potentially life-threatening infections and chronic sequelae (12,13).…”