Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial

beta-Thalassemias are inherited anemias that are caused by the absent or insufficient production of the beta chain of hemoglobin. Here we report 6-8-year follow-up of four adult patients with transfusion-dependent beta-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 (. 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 beta-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.

Automated summary

This study reports the 6-8-year follow-up of four adult patients with transfusion-dependent beta-thalassemia who received autologous CD34(+) cells transduced with a lentiviral globin vector. The findings suggest that non-myeloablative conditioning can achieve durable stem cell engraftment, but a minimum CD34(+) cell transduction requirement is necessary for effective therapy. The study highlights the importance of monitoring patients with globin vectors.