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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\u2019s 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.<\/jats:p>","DOI":"10.1038\/s41375-025-02585-8","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T15:49:04Z","timestamp":1744127344000},"page":"1325-1333","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Current landscape of vector safety and genotoxicity after hematopoietic stem or immune cell gene therapy"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3777-0394","authenticated-orcid":false,"given":"Giorgio","family":"Ottaviano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8353-4494","authenticated-orcid":false,"given":"Waseem","family":"Qasim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,8]]},"reference":[{"key":"2585_CR1","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1126\/science.288.5466.669","volume":"288","author":"M Cavazzana-Calvo","year":"2000","unstructured":"Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, et al. 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WQ declares the following conflicts of interest: research funding from Wellcome Trust, NIHR, MRC; consulting fees from Virocell, Astrazeneca, Wugen; filed patent for therapeutic T cells.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}