Table 3.

Summary of expert concerns and recommendations

Expert concerns/observations	Expert recommendations
There are insufficient data to fully delineate the magnitude of cancer risk; hence, efforts should be made to collectively aggregate, share, and analyze data	•increased focus on the development of standard assays using sequencing based technologies, with acceptable quality-control metrics on reproducibility, sensitivity, and specificity •build and develop unified standards with aggregate data to assess translatability, including consistent use of positive and negative controls •need for alignment on the definition of a clonal expansion •encourage the use of transparent open-source software and universal data sharing •data on potential integration-related severe adverse events should be aggregated in publicly available archives
There is concern surrounding the use of animal models to model potential genotoxicity and whether the findings would be translatable to humans	•animal data need to be well recorded and analyzed for similarities and differences in humans •risk quantification should also delineate the vector type and design
Routine liver biopsies without medical indication should be avoided	•follow-up should include ultrasound scans or MRI and AFP •focus should be on analysis of any tumors detected after gene therapy. Notably, the amount of tissue in a biopsy may not be representative of the whole organ, and would likely be uninformative, containing only randomly integrated AAV, with the exception of tumor biopsies
Given the current lack of observed genotoxicity in large animal models and humans, should patients still be informed and are physicians properly aware of what and when to communicate?	•while AAV-related tumorigenicity has been observed only in mice, vector integration has been observed and measured in large animals and humans, and rAAV must therefore be considered a mutagen •there is a distinct need for bidirectional patient and physician education on the need for informed consent

This summary is based on interviews with the experts Drs. Jessica Zucman-Rossi,^1,2,3 Graham Foster,⁴ Frederic D. Bushman,⁵ Phillip W.L. Tai,⁶ Richard Gabriel,⁷ Mark A. Kay,⁸ Eugenio Montini,⁹ and Charles Venditti.¹⁰

¹Centre de Recherche des Cordeliers, Sorbonne Universités, INSERM, Paris, Île-de-France, France.

²Functional Genomics of Solid Tumor, Labex Immuno-Oncology, équipe labellisée Ligue Contre le Cancer, Université de Paris, Université Paris 13, Paris, Île-de-France, France.

³Department of Oncology, APHP, Hospital Européen Georges Pompidou, Paris, Île-de-France, France.

⁴Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, Surrey, UK.

⁵Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

⁶Horae Gene Therapy Center, Li Weibo Institute for Rare Diseases Research, Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.

⁷ProtaGene CGT GmbH, Heidelberg, Germany.

⁸Departments of Pediatrics and Genetics, Stanford University, Stanford, CA, USA.

⁹San Raffaele Telethon Institute for Gene Therapy, IRCCS Ospedale San Raffaele Scientific Institute, Milan, Italy.

¹⁰National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.