Abstract
Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4–15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7–98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk–benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481, NCT03478670.
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Data availability
All data supporting the findings of this study are available within the paper and its supplementary files. Because of the small number of participants in the studies and potential for identification, individual patient data beyond what is included in the manuscript will not be available. Requests of additional information should be addressed to aiuti.alessandro@hsr.it and will be shared with Fondazione Telethon (the sponsor and Strimvelis license holder) R&D Director, to verify if the request is subject to any intellectual property or confidentiality obligations. Criteria for request evaluations will be scientific merit of the request/intellectual property restrictions/data transfer agreement. The timeline of response will be from 2 to 4 weeks.
References
Hassan, A. et al. Inborn Errors Working Party of the European Group for Blood and Marrow Transplantation and European Society for Immunodeficiency. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood 120, 3615–3624 (2012).
Kreins, A. Y. et al. Long-term immune recovery after hematopoietic stem cell transplantation for ADA deficiency: a single-center experience. J. Clin. Immunol. 42, 94–107 (2022).
Ghimenton, E. et al. Hematopoietic cell transplantation for adenosine deaminase severe combined immunodeficiency—improved outcomes in the modern era. J. Clin. Immunol. 42, 819–826 (2022).
Lankester, A. et al. Hematopoietic cell transplantation in severe combined immunodeficiency: the SCETIDE 2006-2014 European cohort. J. Allergy Clin. Immunol. 149, 1744–1754 (2022).
Geoffrey, D. E. et al. Outcomes following treatment for adenosine deaminase deficient severe combined immunodeficiency: a report from the PIDTC. Blood 140, 685–705 (2022).
Bertaina, A. et al. HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders. Blood 124, 822–826 (2014).
Tucci, F. et al. Emapalumab treatment in an ADA-SCID patient with refractory hemophagocytic lymphohistiocytosis-related graft failure and disseminated bacillus Calmette–Guérin infection. Haematologica 106, 641–646 (2021).
Tsilifis, C. et al. TCRαβ-depleted haploidentical grafts are a safe alternative to HLA-matched unrelated donor stem cell transplants for infants with severe combined immunodeficiency. J. Clin. Immunol. 42, 851–858 (2022).
Migliavacca, M. et al. First occurrence of plasmablastic lymphoma in adenosine deaminase-deficient severe combined immunodeficiency disease patient and review of the literature. Front Immunol. 9, 113 (2018).
Gaspar, H. B. et al. How I treat ADA deficiency. Blood 114, 3524–3532 (2009).
Grunebaum, E. et al. Updated management guidelines for adenosine deaminase deficiency. J. Allergy Clin. Immunol. Pract. 11, 1665–1675 (2023).
Ferrari, G. et al. Gene therapy using haematopoietic stem and progenitor cells. Nat. Rev. Genet. 22, 216–234 (2021).
Kohn, D. B. et al. Autologous ex vivo lentiviral gene therapy for adenosine deaminase deficiency. N. Engl. J. Med. 384, 2002–2013 (2021).
Lankester, A. C. et al. EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity. Bone Marrow Transplant. 56, 2052–2062 (2021).
Aiuti, A. et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N. Engl. J. Med. 360, 447–458 (2009).
Cicalese, M. P. et al. Gene therapy for adenosine deaminase deficiency: a comprehensive evaluation of short- and medium-term safety. Mol. Ther. 26, 26917–26931 (2018).
Cicalese, M. P. et al. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood 128, 45–54 (2016).
Aiuti, A. et al. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol. Med. 9, 737–740 (2017).
Lawrence, M. G. et al. Elevated IgE and atopy in patients treated for early-onset ADA-SCID. J. Allergy Clin. Immunol. 132, 1444–1446 (2013).
Fratini, E. S. et al. Hemophagocytic inflammatory syndrome in ADA-SCID: report of two cases and literature review. Front. Immunol. 14, 1187959 (2023).
Canarutto, D. et al. Outcome of BCG vaccination in ADA-SCID patients: a 12-patient series. Biomedicines 11, 1809 (2023).
Tucci, F. et al. Bone marrow harvesting from paediatric patients undergoing haematopoietic stem cell gene therapy. Bone Marrow Transplant. 54, 1995–2003 (2019).
Grunebaum, E. et al. Purine metabolism, immune reconstitution, and abdominal adipose tumor after gene therapy for adenosine deaminase deficiency. J. Allergy Clin. Immunol. 127, 1417–1419 (2011).
Aiuti, A. et al. Ensuring a future for gene therapy for rare diseases. Nat. Med. 28, 1985–1988 (2022).
Reinhardt, B. C. et al. Long-term outcomes after gene therapy for adenosine deaminase severe combined immune deficiency. Blood 138, 1304–1316 (2021).
Sokolic, R. et al. Myeloid dysplasia and bone marrow hypocellularity in adenosine deaminase deficient severe combined immune deficiency. Blood 118, 2688–2694 (2011).
Starc, N. et al. Biological and functional characterization of bone marrow-derived mesenchymal stromal cells from patients affected by primary immunodeficiency. Sci. Rep. 7, 8153 (2017).
Cavazzana, M. et al. Gene therapy with hematopoietic stem cells: the diseased bone marrow’s point of view. Stem Cells Dev. 26, 71–76 (2017).
Gaspar, B. Gene therapy for ADA-SCID: defining the factors for successful outcome. Blood 120, 3628–3629 (2012).
Sauer, A. V. et al. New insights into the pathogenesis of adenosine deaminase-severe combined immunodeficiency and progress in gene therapy. Curr. Opin. Allergy Clin. Immunol. 9, 496–502 (2009).
Malvagia, S. et al. The successful inclusion of ADA SCID in Tuscany expanded newborn screening program. Clin. Chem. Lab. Med. 59, e401–e404 (2021).
Thakar, M.S. et al. Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium. Lancet 402, 129–140 (2023).
Kim, V. H.-D. et al. Neutropenia among patients with adenosine deaminase deficiency. J. Allergy Clin. Immunol. 143, 403–405 (2019).
Sauer, A. V. et al. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood 114, 3216–3226 (2009).
Canarutto, D. et al. Peripheral blood stem and progenitor cell collection in pediatric candidates for ex vivo gene therapy: a 10-year series. Mol. Ther. Methods Clin. Dev. 22, 76–83 (2021).
Sauer, A. V. et al. Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients. Sci. Rep. 11, 40136 (2017).
Pajno, R. et al. Urogenital abnormalities in adenosine deaminase deficiency. J. Clin. Immunol. 40, 610–618 (2020).
Burgio, G. R., Perinotto, G. & Ugazio, A. G. Pediatria Essenziale (UTET, 1991).
Carlucci, F. et al. Evaluation of ADA gene expression and transduction efficiency in ADA/SCID patients undergoing gene therapy. Nucleosides Nucleotides Nucleic Acids 23, 1245–1248 (2004).
Aiuti, A. et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science 296, 2410–2413 (2002).
Cassani, B. et al. Integration of retroviral vectors induces minor changes in the transcriptional activity of T cells from ADA-SCID patients treated with gene therapy. Blood 114, 3546–3561 (2009).
Tucci, F. et al. Successful treatment with ledipasvir/sofosbuvir in an infant with severe combined immunodeficiency caused by adenosine deaminase deficiency with HCV allowed gene therapy with Strimvelis. Hepatology 68, 2434–2437 (2018).
Acknowledgements
We acknowledge Fondazione Telethon for continuous support and strategic guidance; the nursing team of the Pediatric Immunohematology Unit, Stem Cell Transplant Program of the IRCCS San Raffaele Scientific Institute, for their professional care of patients during hospitalization; the staff of the Ospedale San Raffaele Stem Cell Program for support to patients; L. Castagnaro and the quality-assurance team; the team of the Department of Anesthesia for support; all the research nurses; M. Soncini and all of the Sr-Tiget clinical lab for their support; G. Tomaselli and L. Meroni for administrative assistance; S. El Hossari and cultural mediators; all personnel and volunteers of the Fondazione Telethon ‘Just Like Home’ Program for their constant support of families and their care of the children; the staff of the SR-Tiget Clinical Trial Office for their support in trial management; the SR-Tiget clinical lab; and the team of AGC Biologics (formerly MolMed) for manufacturing the vector and medicinal product. The work was partially supported by Fondazione Telethon and grants from the European Commission (ERARE-3-JTC 2015 EUROCID, A.A.), Ministero della Salute, Ricerca Finalizzata NET-2011-02350069 (to A.A. and C.C.). A.A. is the recipient of Else Kröner-Fresenius-Stiftung (EKFS) prize. I.M. is a senior clinical investigator at FWO Vlaanderen, and is supported by a KU Leuven C1 Grant C16/18/007 and by a VIB GC PID Grant. Several authors are members of the European Reference Network for Rare Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN-RITA); Inborn Error Working Party of EBMT and Italian Primary Immunodeficiencies Network (IPINET); and Associazione Italiana Ematologia e Oncologia Pediatrica (AIEOP). We thank the patients and families who have been treated in both the experimental and approved phases and those who are currently followed up in the STRIM registry, all the primary physicians from countries worldwide who referred patients and continued their F-U with great commitment.
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M.M. contributed to the study design, patients’ F-U, data collection, interpretation and manuscript writing. F.B. contributed to the study design, patient F-U, data collection and interpretation. C.F. contributed to data collection and analysis. P.M.V.R. and C.D.S. contributed to data analysis. M. Gabaldo, A.C. and S.Z. contributed to data collection and regulatory applications. F.D., S.G., F.A.S., I. Monti, D.C. and F. Carlucci performed molecular, biochemical and immunological analysis and interpretation. F.F., F.T., V.C., V. Gallo, S.R., G.C., M.S., A.P. and M.E.B. contributed to patient F-U and data collection. C.F. and V. Garella contributed to data collection and analysis. P. Silvani was responsible for the procedures under anesthesia of the patients. S.D. and M.C. assisted patients and their families as research nurse. M.L. coordinated the logistics, travels and cultural mediation of patients and their families. D.A., U.B., A.F., C.C., S.L., A.M., I. Meyts, D.M., L.D.N., F.P., M.P., C.S., P. Stepensky, A.T., M.R., Z.K., M. Galicchio, L.L., M.D., A.P.-N. and S.N.G. referred and followed patients for GT treatment and provided data. F. Ciceri provided support to GT treatments within the Stem Cell Program of IRCCS Ospedale San Raffaele, Milan. M.P.C. and A.A. contributed to the study design, patients’ F-U, data collection and interpretation, and manuscript writing and provided overall supervision. Each author made substantial contributions to the present work, approved the submitted version and agreed both to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated and resolved, and the resolution documented in the literature.
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The San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) is a joint venture between the Telethon Foundation and Ospedale San Raffaele (OSR). GT for ADA-SCID was developed at SR-Tiget and licensed to GlaxoSmithKline (GSK) in 2010. The treatments under NPP and HE were provided free of charge by GSK. Strimvelis Marketing Authorization in Europe occurred in 2016 (under GSK holding) and then transferred to Orchard Therapeutics (Netherlands) B.V. in 2018, which divested the program and transferred the authorization to Fondazione Telethon that became the holder in July 2023. The product, apart from the EU, is also currently approved in Iceland, Norway, Liechtenstein and the United Kingdom. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. A.A. receives funding from Fondazione Telethon for other research projects. A.A. was the PI of pilot, pivotal and long-term F-U study of SR-Tiget clinical trials of gene therapy for ADA-SCID. M.P.C. and M.M. are PI and deputy PI, respectively, of the Strimvelis Registry, RIS and RMMs studies. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 In vivo engraftment of genetically corrected cells.
(A) Cumulative incidence of neutrophil engraftment. Curves represent time to achieve neutrophil engraftment (3 consecutive days of ANC ≥ 500) after gene therapy in the CDP + NPP and STRIM cohort. (B; C) Longitudinal analysis of absolute neutrophil count with respect to CD3 + VCN (B) and lymphocytes (C) in CDP + NPP and STRIM patients. The neutrophil trend was estimated by using mixed-effects models with fractional polynomials, evaluating its dependency either on CD3 + VCN or lymphocytes. Only data up to 36 months after gene therapy were used and data of both CDP + NPP and Strimvelis groups were considered together. ANC: absolute neutrophil count; VCN: Vector Copy Number.
Extended Data Fig. 2 Neutrophil engraftment and longitudinal analyses.
Persistent multilineage engraftment of genetically corrected cells in peripheral blood in STRIM (A, C, E, G) and CDP + NPP (B, D, F, H) patients. In the plots, box and whiskers display the median, the first and the third quartile and the minimum and the maximum of the data. The number of patients contributing to each data point is indicated on the graph. CD3+ cells (A-B), CD19+ cells (C-D), CD56+ cells (E-F), CD15+ cells (G-H), were purified from peripheral blood. VCN=vector copy number; d=day; y=year.
Extended Data Fig. 3 Longitudinal analysis comparing engraftment, immune reconstitution and metabolic correction in CDP + NPP and Strimvelis patients.
The longitudinal trends were estimated and compared between groups, by using mixed-effects models with fractional polynomials due to their nonlinear shape (see Supplementary Statistical Methods and Supplementary Tables S4a–f). Only data up to 36 months after gene therapy were used. Graphs represent estimated longitudinal trend of CD15+ cells VCN (A), CD3+ cells VCN (B), lymphocyte counts (C), CD3 + T cell counts (D) CD4 + CD45RA+ naïve T-cell counts (E) and dAXP in RBC (F). dAXP: deoxyadenosine nucleotides; RBC: red blood cells.
Extended Data Fig. 4 Cumulative incidence of lymphocyte and T cells normalizations.
Curves represent the cumulative incidence of achieving normal lymphocyte counts (A) or CD3 + T cells counts (B) after gene therapy in the CDP + NPP and STRIM cohort, according to normal age values.
Extended Data Fig. 5 In vitro T-cell functions in CDP + NPP and STRIM populations.
Proliferative T-cell capacity assessed following challenge with anti-CD3 antibody (A, B, C) or PHA (D, E, F) in CDP + NPP and STRIM populations by observation period and expressed as Stimulation Index. In the plots, box and whiskers display the median, the first and the third quartile and the minimum and the maximum of the data. Analyses of data at the time-points baseline and 3 year are reported in the Supplementary Statistical Methods and Supplementary Tables S6a–d. SI: stimulation index; PHA: phytohemagglutinin.
Extended Data Fig. 6 In vivo engraftment of genetically corrected cells, immune reconstitution and metabolic correction in patients receiving mobilized peripheral blood-derived CD34+ cells.
Multilineage engraftment and immune reconstitution in 2 patients treated under hospital exemption (HE) with mobilized peripheral blood (MPB)-derived CD34+ cells up to 4 years of F-U. Graphs show: VCN in CD15+ (A), CD3+ (B), CD19+ (C) and CD56+ cells (D) purified from peripheral blood; absolute cell counts (cells/uL) of lymphocytes (E) CD3+ (F), CD3 + CD4+ (G), CD3 + CD8+ (H), CD4 + CD45RA+ (I), CD19+ (J), CD16 + CD56+ (K) in peripheral blood. The shaded dark and light grey regions represent median and fifth percentile values, respectively, in normal children. The top edges correspond to levels in children ages 2 to 5 years; bottom edges correspond to levels in children ages 10 to 16 years. Values for children ages 5 to 10 typically fall within the shaded areas (Comans-Bitter, WM et al: Immunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulation. J Pediatr, 130: 3388-393 (1997)). in vitro T-cell proliferation response (expressed as SI) after anti-CD3i stimulation (L), by observation period. dAXP in red blood cells (RBC) (M) and ADA activity in mononuclear cells (MNC) (N). Dashed lines indicate the lower reference value of ADA activity/dAXP for patients undergone successful hematopoietic stem cell transplantation. VCN=vector copy number; d=day; y=year. SI: stimulation index.
Supplementary information
Supplementary Information
Supplementary Tables 1, 2 and S1–S7, Figs. 1–5 and statistical analysis.
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Migliavacca, M., Barzaghi, F., Fossati, C. et al. Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency. Nat Med 30, 488–497 (2024). https://doi.org/10.1038/s41591-023-02789-4
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DOI: https://doi.org/10.1038/s41591-023-02789-4
