A phase 1 trial of lentiviral globin gene therapy with reduced intensity conditioning in adults with transfusion dependent β-thalassemia

• Published in: Nature medicine Vol. 28; no. 1; pp. 63 - 70
• Main Authors: Boulad, Farid, Maggio, Aurelio, Wang, Xiuyan, Moi, Paolo, Acuto, Santina, Kogel, Friederike, Takpradit, Chayamon, Prockop, Susan, Mansilla-Soto, Jorge, Cabriolu, Annalisa, Odak, Ashlesha, Qu, Jinrong, Thummar, Keyur, Du, Fang, Shen, Lingbo, Raso, Simona, Barone, Rita, Di Maggio, Rosario, Pitrolo, Lorella, Giambona, Antonino, Mingoia, Maura, Everett, John K., Hokama, Pascha, Roche, Aoife M., Cantu, Vito Adrian, Adhikari, Hriju, Reddy, Shantan, Bouhassira, Eric, Mohandas, Narla, Bushman, Frederic D., Rivière, Isabelle, Sadelain, Michel
• Format: Journal Article
• Language: English
• Published: 01.01.2022
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-021-01554-9

The β-thalassemias are inherited anemias that are caused by the absent or insufficient production of the ß chain of hemoglobin. 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 I clinical trial ( NCT01639690 ). Patients were monitored for insertional mutagenesis and the generation of a replication-competent lentivirus (RCL) (safety and tolerability of the infusion product following RIC; primary endpoint) and engraftment of the genetically modified autologous CD34+ cells, the expression of the transduced β-globin gene, and the post-transplant transfusions 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 to cautiously monitor patients harboring globin vectors.