Current landscape of vector safety and genotoxicity after hematopoietic stem or immune cell gene therapy

• Published in: Leukemia Vol. 39; no. 6; pp. 1325 - 1333
• Main Authors: Ottaviano, Giorgio, Qasim, Waseem
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.06.2025; Nature Publishing Group UK
• Subjects: Animals; Clinical trials; DNA Damage; Gene therapy; Genetic modification; Genetic Therapy - adverse effects; Genetic Therapy - methods; Genetic transformation; Genetic Vectors - adverse effects; Genetic Vectors - genetics; Genotoxicity; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic Stem Cell Transplantation - methods; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Humans; Immune system; Lymphocytes; Lymphocytes T; Malignancy; Review; Risk reduction; Stem cells
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-025-02585-8

Malignant transformation of gene modified haematopoietic stem cells caused anxiety following adverse events in early clinical trials using gamma-retroviral vectors (γRV) to correct haematopoietic stem cells (HSC) in monogenic immune disorders. Adoption of HIV-derived lentiviral vectors (LV) with SIN (self-inactivating) configurations greatly reduced risks and subsequently hundreds of patients have been dosed with HSC gene therapy for blood, immune and metabolic conditions. Nevertheless, as experience builds, it’s now well recognised that vector integration can drive clonal expansions and these may carry long term safety risks. Documented cases of haematological malignancy after SIN-LV gene therapy have recently emerged, in particular where heterologous retroviral promoters were employed and there are concerns around certain insulator elements and other possible contributors to clonal expansions. Similarly, tens of thousands of subjects have now received engineered T cell products, and longstanding dogma that mature T cells cannot be transformed is being questioned, with reports of a small number of malignant transformation events and wider concerns around secondary malignancies in some groups of patients. We summarize current clinical information and revisit genotoxicity risks following ex-vivo gene modification of HSC and T cells.