@article{cd3fd4a3e4284e98848bdc111a61437d,
title = "Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial",
abstract = "β-Thalassemias are inherited anemias that are caused by the absent or insufficient production of the β chain of hemoglobin. Here we report 6–8-year follow-up of four adult patients with transfusion-dependent β-thalassemia who were infused with autologous CD34+ cells transduced with the TNS9.3.55 lentiviral globin vector after reduced-intensity conditioning (RIC) in a phase 1 clinical trial (NCT01639690). Patients were monitored for insertional mutagenesis and the generation of a replication-competent lentivirus (safety and tolerability of the infusion product after RIC—primary endpoint) and engraftment of genetically modified autologous CD34+ cells, expression of the transduced β-globin gene and post-transplant transfusion requirements (efficacy—secondary endpoint). No unexpected safety issues occurred during conditioning and cell product infusion. Hematopoietic gene marking was very stable but low, reducing transfusion requirements in two patients, albeit not achieving transfusion independence. Our findings suggest that non-myeloablative conditioning can achieve durable stem cell engraftment but underscore a minimum CD34+ cell transduction requirement for effective therapy. Moderate clonal expansions were associated with integrations near cancer-related genes, suggestive of non-erythroid activity of globin vectors in stem/progenitor cells. These correlative findings highlight the necessity of cautiously monitoring patients harboring globin vectors.",
author = "Farid Boulad and Aurelio Maggio and Xiuyan Wang and Paolo Moi and Santina Acuto and Friederike Kogel and Chayamon Takpradit and Susan Prockop and Jorge Mansilla-Soto and Annalisa Cabriolu and Ashlesha Odak and Jinrong Qu and Keyur Thummar and Fang Du and Lingbo Shen and Simona Raso and Rita Barone and {Di Maggio}, Rosario and Lorella Pitrolo and Antonino Giambona and Maura Mingoia and Everett, {John K.} and Pascha Hokama and Roche, {Aoife M.} and Cantu, {Vito Adrian} and Hriju Adhikari and Shantan Reddy and Eric Bouhassira and Narla Mohandas and Bushman, {Frederic D.} and Isabelle Rivi{\`e}re and Michel Sadelain",
note = "Funding Information: The authors would first like to thank the patients and families of those included in the trial and further acknowledge the expert care provided to patients by staff members of the Department of Pediatrics at Memorial Sloan Kettering Cancer Center. We thank R. Cristantielli, G. Gunset and E. Bechard for their further assistance in making our patients{\textquoteright} journeys and their follow-up pleasant and efficient. This clinical trial was supported by the Stavros Niarchos Foundation (to M.S.), the Memorial Hospital Research Fund (to F.B.), the Leonardo Giambrone Foundation (to M.S.) and the Cooley{\textquoteright}s Anemia Foundation (to M.S.) for transduction, biosafety and clinical costs, and Errant Gene Therapy (to M.S.) for the TNS9.3.55 vector lot, produced at the Center for Biomedicine and Genetics in Duarte, California, and the MSKCC Support Grant (P30 CA008748). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We also thank S. Avecilla, Q. He, C. Taylor, M. Fink, T. Wasielewska, S. Bartido, Y. Wang and the members of the Cell Therapy and Cell Engineering Facility who, for 7 years, have assisted in the manufacturing and monitoring of the CD34+ cell infusion products for our patients. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = jan,
doi = "10.1038/s41591-021-01554-9",
language = "English (US)",
volume = "28",
pages = "63--70",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "1",
}
