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Gene Therapy And Secondary Malignancies: Integration Site Analysis Can Only Be Part Of The Answer

 
• By Bridget Silverman

The US FDA seeks to better understand and predict insertional mutagenesis in gene therapies like bluebird bio's Skysona, which use integrating viral vectors, but a workshop on integration site analysis highlighted the approach's complexity and limitations.

Integrating viral vectors allow for persistent effects of gene therapies, but risk insertional mutagenesis. (Shutterstock)
Key Takeaways
  • Integration site analysis can identify vector insertion sites in the genome of patients who receive gene therapies with integrating viral vectors, but the FDA wants to refine the standards and methods for using the complex technique to assess the risk of secondary malignancies.
  • ISA was part of the surveillance that resulted in a 27 November FDA safety communication about additional reports of hematologic malignancies with bluebird bio's Skysona, but the low number of patients highlights the difficulty of discerning risk patterns within the diverse group of CAR-T and gene therapies that employ integrating viral vectors.
  • Integration site analysis is more useful as a retrospective research tool than for patient monitoring, speakers said during a recent workshop.

The scope and technical complexity of assessing the risk of secondary malignancies in gene therapy recipients looms over the US Food and Drug Administration’s focus on the role of insertion...

Gene therapies employing integrating viral vectors, most commonly lentiviral or gammaretroviral vectors, permanently modify the genomes of target cells. Given the persistence of the effect, “understanding the relationship between therapies...

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