Over 10% of patients treated with bluebird bio’s gene therapy Skysona (elivaldogene autotemcel) for cerebral adrenoleukodystrophy (CALD) have developed hematological cancers, raising concerns about the long-term safety of lentiviral vector-based gene therapies. The findings highlight the known risks associated with using lentiviral vectors in gene therapy.
Details of Cancer Development
The patients, who were treated with Skysona to slow the progression of CALD, a rare X-linked neurodegenerative disease, developed myelodysplastic syndrome (six patients) or acute myeloid leukemia (one patient) between 14 and 92 months after treatment. Skysona comprises autologous CD34+ cells engineered ex vivo to express the ABCD1 gene, which is deficient in individuals with CALD, leading to toxic build-up of fatty acids in the brain, spinal cord, and adrenal glands.
Vector Insertion and Proto-oncogenes
Skysona utilizes a replication-deficient, HIV-1-derived vector named Lenti-D, containing the synthetic promoter MNDU3, designed for strong gene expression across multiple cell types. A significant finding was the association of six cancer cases with the expansion of a cell clone containing at least one vector insertion in a known proto-oncogene. Specifically, five cases involved insertions in MECOM, and one in its closely related homologue PRDM16.
Potential Contributing Factors
While the lentiviral vector is implicated, the study authors suggest that the myeloablative conditioning regimen might also be a contributing factor. Six of the seven cases occurred in the ALD-104 study, where participants received busulfan and fludarabine, whereas the ALD-102 study used busulfan and cyclophosphamide.
Clinical Context and Outcomes
Despite the development of cancer in some patients, the study is considered a clinical success given the severity and life-threatening nature of CALD. It was reported that the patients who developed cancer were treated successfully, except for one who died after developing graft-versus-host disease and a lung infection. However, the possibility of further cancer cases cannot be eliminated, necessitating long-term monitoring of patients treated with Skysona.
