Insertional oncogenesis in gene therapy: how much of a risk?

Insertional mutagenesis is an unavoidable consequence of the transposition of genetic material. Whether it involves an integrating virus, a transposable element, a replicationdefective viral vector or plasmid DNA, the ectopic chromosomal integration of DNA is a mutagenic event that may disrupt chromatin or gene structure, thereby altering gene transcription, regulation and/or coding sequences. The gravest concern associated with such mutations is the risk of cell transformation. The acquisition of the malignant phenotype may follow tumor suppressor gene inactivation, typically a recessive event, or oncogene trans-activation, which is likely to exert a dominant effect. The propensity of transposable elements to induce experimental tumors in animals has long been exploited to study the genetic basis of cancer. The earliest analyses of the therapeutic potential of gene transfer have thus recognized the risk of insertional oncogenesis as inherent to the use of integrating vectors. Yet, there have been extremely few reports documenting insertional oncogenesis in rodent, dog and non-human primate gene transfer studies. Based on these experimental data, gene therapists and their patients have justifiably assumed that the risk of insertional oncogenesis would be very low. This reassuring point of view was challenged last year when the firstever case of iatrogenic malignant transformation was reported in a gene therapy patient treated for Xlinked severe combined immune deficiency (SCID). The consternation brought upon by this serious adverse event (SAE), which shook the medical community and the concerned regulatory agencies, was compounded, but also mitigated, when a second case was reported 6 months later – in the same trial. These two SAEs imposed a reevaluation of the safety concerns associated with gene transfer and of the risk benefit ratio of gene therapy in the context of SCID as well as other diseases. Following a temporary hold on gene therapy trials using retroviral vectors to transduce hematopoietic stem cells, the US Food and Drug Administration and the NIH Recombinant DNA Advisory Committee judiciously concluded that this pair of SAEs did not constitute ground for the cessation of gene therapy investigation. The interrupted trials were therefore allowed to reopen, pending the case-by-case re-evaluation of the risk/benefit ratio for every study and the appropriate revision of the monitoring plans and of the information provided to prospective patients before obtaining informed consent. The prompt resumption of these trials is good news for the field, but the need to reassess the safety of the many gene transfer strategies under development remains. Our understanding of the biological mechanisms that determine, in qualitative and quantitative terms, the risk of clonal expansion and transformation, is still fragmentary. However, two recent reports provide valuable insight into the transforming mechanisms that may have operated in the two SCID patients who developed clonal T-cell expansions. Based on these observations, we can begin to identify possible factors that increase the risk that insertional mutagenesis will turn into oncogenesis. While prospective studies are direly needed to analyze and quantify the role of these risk factors, the reports by HaceinBey-Abina et al and Dave et al provide important clues for taking steps to investigate and reduce the risk of oncogene trans-activation by integrating gene transfer vectors. Gene therapy of X-linked SCID: landmark success and two SAEs