Journal Article

Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency

Tommasini, Alberto, Fossati, Claudia, Consiglieri, Giulia, Galicchio, Miguel, Calbi, Valeria, Giannelli, Stefania, Stepensky, Polina, Levi, Margherita, Speckmann, Carsten, Pajno, Roberta, Garella, Vittoria, Monti, Ilaria, Sambuco, Maria, Finocchi, Andrea, Migliavacca, Maddalena, Zancan, Stefano, Pituch-Noworolska, Anna, Montin, Davide, Casiraghi, Miriam, Meyts, Isabelle, Karakas, Zeynep, Dionisio, Francesca, Meinhardt, Andrea, Notarangelo, Lucia Dora, Rancoita, Paola M. V., Corti, Ambra, Aiuti, Alessandro, Gabaldo, Michela, Guner, Sukru Nail, Di Serio, Clelia, Baumann, Ulrich, Cicalese, Maria Pia, Ferrua, Francesca, Barzaghi, Federica, Pasquet, Marlène, Tucci, Francesca, Ciceri, Fabio, AbdElaziz, Dalia, Gallo, Vera, Bernardo, Maria Ester, Leonardi, Lucia, Rabusin, Marco, Porta, Fulvio, Recupero, Salvatore, Ferri, Chiara, Silvani, Paolo, Duse, Marzia, Cesana, Daniela, Ladogana, Saverio, Darin, Silvia, Cancrini, Caterina, Priolo, Alessio, Salerio, Federica Andrea, Carlucci, Filippo

2024

Overview

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 . Fifteen years’ follow-up of clinical development and real-world data from 43 patients show that gammaretroviral gene therapy for adenosine deaminase deficiency has a positive long-term efficacy profile, warranting continued safety monitoring of patients receiving gene therapy.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/249/2512 / 692/699/249/1570/1921 / 692/700/155 / 692/700/565/201 / Adenosine / Adenosine Deaminase / Adenosine Deaminase - genetics / Adenosine Deaminase - therapeutic use / Agammaglobulinemia / Biomedical and Life Sciences / Biomedicine / Bone marrow / Busulfan / Busulfan - adverse effects / Cancer / Cancer Research / CD3 antigen / CD34 antigen / CD4 antigen / CD45RA antigen / Clinical trials / Conditioning / Detoxification / Effectiveness / Gene therapy / Genetic Therapy / Hematopoietic Stem Cell Transplantation / Hematopoietic stem cells / Humans / Immune reconstitution / Infectious Diseases / Leukemia / Life Sciences / Lymphocytes / Lymphocytes T / Metabolic Diseases / Molecular Medicine / Monitoring / Neurosciences / Patients / Peripheral blood / Remission / Retroviridae / Retroviridae - genetics / Safety / Severe Combined Immunodeficiency / Severe Combined Immunodeficiency - genetics / Severe Combined Immunodeficiency - therapy / Stem cell transplantation / Stem cells / Telemedicine