Lentiviral Gene Therapy for Severe Leukocyte Adhesion Deficiency Type 1.

BACKGROUND The β2 common integrin subunit CD18 is essential for leukocyte-endothelial adhesion and extravasation to inflamed or infected tissue. Damaging variants in ITGB2, which encodes CD18, cause leukocyte adhesion deficiency type I (LAD-I), an inborn error of immunity that leads to frequent life-threatening infections and a high risk of death among affected children. Allogeneic hematopoietic stem-cell transplantation (HSCT) represents a curative treatment but is limited by donor availability, a high incidence of graft-versus-host disease, and graft failure. METHODS In a phase 1-2, multinational, open-label study, we enrolled nine children who had severe LAD-I and treated them with marnetegragene-autotemcel (marne-cel), a gene therapy of autologous CD34+ hematopoietic stem cells transduced with a self-inactivating lentiviral vector containing human ITGB2, and followed them for 24 months. The primary efficacy end point of the phase 2 study was survival without allogeneic HSCT (HSCT-free survival) at least 1 year after marne-cel infusion and at 2 years of age among the patients who were younger than 1 year of age at enrollment, tested against a null hypothesis of survival of 39% of the patients. We also report interim data from six patients enrolled in the long-term follow-up study. RESULTS Serious adverse events related to myeloablative busulfan conditioning were observed. No adverse events attributed to gene therapy were reported. None of the patients had graft failure. HSCT-free survival was 100% (95% confidence interval [CI], 66 to 100) at 1 year after infusion (P<0.001). All the patients who were enrolled at younger than 1 year of age were alive beyond 2 years of age. Pretreatment neutrophilia and skin abnormalities related to LAD-I resolved. The annualized incidence of infection-related hospitalizations beyond 90 days after engraftment through 24 months after marne-cel infusion was 74.45% lower than the incidence before marne-cel infusion, the annualized incidence of prolonged infection-related hospitalizations was 81.95% lower, and the annualized incidence of prespecified serious infections was 84.90% lower. CONCLUSIONS In this study, lentiviral vector-transduced autologous CD34+ HSCT was successful in treating severe LAD-I. (Funded by Rocket Pharmaceuticals and the California Institute for Regenerative Medicine; ClinicalTrials.gov numbers, NCT03812263 and NCT06282432.).