Extensive gene therapy studies in preclinical models and in clinical trials 
underscore the relative safety of onco-retroviral vectors. Up until recently, no 
adverse effects have been reported in nearly 2000 patients that were enrolled in 
gene therapy clinical trials involving onco-retroviral vectors. However, the 
main safety concern of using onco-retroviral vectors is related to the risk of 
malignant transformation following oncogene activation due to random 
onco-retroviral genomic integration. Based on primate studies, there is an 
apparent low risk of malignancy that is predominately associated with the 
occurrence of chronic retroviremia resulting from replication-competent 
retroviruses (RCR), particularly in immunosuppressed recipient hosts. However, 
in the latest packaging cell lines and vectors, the risk of RCR-generation has 
been drastically reduced, primarily by minimizing the homologous overlap between 
vector and helper sequences. Nevertheless, results from a recent preclinical 
study in mice and a clinical trial in patients suffering from SCID-X1 strongly 
suggest that onco-retroviral vectors devoid of RCR can contribute to 
lymphomagenesis by insertional activation of cellular oncogenes. The risk of 
inadvertent germline transmission of onco-retroviral vectors appears to be low, 
especially relative to the endogenous rate of germline insertion, which is known 
to occur naturally in the human population via transmission of endogenous 
retro-transposons. The strict dependency of onco-retroviral gene transfer on 
cell division is an important safety advantage that significantly limits the 
risks of horizontal transmission. Since improved onco-retroviral vectors or 
transduction protocols may result in an increased number of retroviral 
integrations per cell, this may concomitantly increase the risk of malignant 
transformation. The use of suicide genes, self-inactivating vectors and/or 
chromosomal insulators is, therefore, warranted to further enhance the safety 
features of onco-retroviral vectors. Detailed analyses of insertion sites 
combined with long-term clinical follow-up may contribute to a more accurate 
risk assessment.