Improving the Assessment of Risk Factors Relevant to Potential Carcinogenicity of Gene Therapies: A Consensus Article

Jan C Klapwijk¹, Alberto Del Rio Espinola², Silvana Libertini³, Philippe Collin⁴, Mick D Fellows⁴, Susan Jobling^{5

6}, Anthony M Lynch⁷, HansJoerg Martus³, Catherine Vickers⁸, Andreas Zeller⁹, Luca Biasco¹⁰, Martijn H Brugman¹¹, Frederic D Bushmann¹², Toni Cathomen^{13

14}, Hildegrund C J Ertl¹⁵, Richard Gabriel¹⁶, Guangping Gao¹⁷, Julie K Jadlowsky¹⁸, Ian Kimber¹⁹, Thomas A Lanz²⁰, Bruce L Levine¹⁸, Kenneth P Micklethwaite^{21

22

23

24}, Masafumi Onodera²⁵, Daniella M Pizzurro²⁶, Simon Reed²⁷, Michael Rothe²⁸, Denise E Sabatino^{29

30}, Jesse J Salk^{31

32}, Axel Schambach^{28

33}, Michael Themis^{5

6}, Jing Yuan³⁴

Affiliations

¹ Cornelis Consulting Ltd, London, United Kingdom.
² GentiBio Inc., Cambridge, Massachusetts, USA.
³ Novartis Biomedical Research, Basel, Switzerland.
⁴ Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom.
⁵ TestaVec Ltd, Maidenhead, United Kingdom.
⁶ Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom.
⁷ GlaxoSmithKline, Genetic Toxicology, Ware, United Kingdom.
⁸ National Centre for the Replacement Refinement and Reduction of Animals in Research, London, United Kingdom.
⁹ F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
¹⁰ UCL Zayed Centre for Research (ZCR), London, United Kingdom.
¹¹ Cell and Gene Therapy, GSK Medicine Research Centre, Stevenage, United Kingdom.
¹² Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, Pennsylvania, USA.
¹³ Institute for Transfusion Medicine and Gene Therapy, Medical Center- University of Freiburg, Freiburg, Germany.
¹⁴ Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹⁵ Ertl Laboratory, Vaccine & Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.
¹⁶ ProtaGene CGT, Heidelberg, Germany.
¹⁷ Horae Gene Therapy Center, UMass Chan Medical School, University of Massachusetts, Worcester, Massachusetts, USA.
¹⁸ Center for Cellular Immunotherapies and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁹ Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
²⁰ Drug Safety Research & Development, Pfizer, Inc., Groton, Connecticut, USA.
²¹ Department of Haematology, Blood Transplant and Cell Therapies Program, Westmead Hospital, Sydney, Australia.
²² NSW Health Pathology Blood Transplant and Cell Therapies Laboratory - ICPMR Westmead, Sydney, Australia.
²³ Westmead Institute for Medical Research, Sydney, Australia.
²⁴ Sydney Medical School, The University of Sydney, Sydney, Australia.
²⁵ Gene & Cell Therapy Promotion Center, National Center for Child Health and Development, Tokyo, Japan.
²⁶ Merck & Co., Inc., Boston, Massachusetts, USA.
²⁷ Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
²⁸ Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
²⁹ Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³⁰ The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³¹ Department of Medicine, Divisions of Hematology and Medical Oncology, University of Washington School of Medicine, Seattle, Washington, USA.
³² TwinStrand Biosciences Inc., Seattle, Washington, USA.
³³ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³⁴ Kymera Therapeutics, Watertown, Massachusetts, USA.

PMID: 39049734
DOI: 10.1089/hum.2024.033

Free article

Review

Improving the Assessment of Risk Factors Relevant to Potential Carcinogenicity of Gene Therapies: A Consensus Article

Jan C Klapwijk et al. Hum Gene Ther. 2024 Aug.

Free article

. 2024 Aug;35(15-16):527-542.

doi: 10.1089/hum.2024.033.

Authors

Affiliations

¹ Cornelis Consulting Ltd, London, United Kingdom.
² GentiBio Inc., Cambridge, Massachusetts, USA.
³ Novartis Biomedical Research, Basel, Switzerland.
⁴ Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom.
⁵ TestaVec Ltd, Maidenhead, United Kingdom.
⁶ Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom.
⁷ GlaxoSmithKline, Genetic Toxicology, Ware, United Kingdom.
⁸ National Centre for the Replacement Refinement and Reduction of Animals in Research, London, United Kingdom.
⁹ F. Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, Roche Innovation Center Basel, Basel, Switzerland.
¹⁰ UCL Zayed Centre for Research (ZCR), London, United Kingdom.
¹¹ Cell and Gene Therapy, GSK Medicine Research Centre, Stevenage, United Kingdom.
¹² Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, Pennsylvania, USA.
¹³ Institute for Transfusion Medicine and Gene Therapy, Medical Center- University of Freiburg, Freiburg, Germany.
¹⁴ Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹⁵ Ertl Laboratory, Vaccine & Immunotherapy Center, The Wistar Institute, Philadelphia, Pennsylvania, USA.
¹⁶ ProtaGene CGT, Heidelberg, Germany.
¹⁷ Horae Gene Therapy Center, UMass Chan Medical School, University of Massachusetts, Worcester, Massachusetts, USA.
¹⁸ Center for Cellular Immunotherapies and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁹ Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
²⁰ Drug Safety Research & Development, Pfizer, Inc., Groton, Connecticut, USA.
²¹ Department of Haematology, Blood Transplant and Cell Therapies Program, Westmead Hospital, Sydney, Australia.
²² NSW Health Pathology Blood Transplant and Cell Therapies Laboratory - ICPMR Westmead, Sydney, Australia.
²³ Westmead Institute for Medical Research, Sydney, Australia.
²⁴ Sydney Medical School, The University of Sydney, Sydney, Australia.
²⁵ Gene & Cell Therapy Promotion Center, National Center for Child Health and Development, Tokyo, Japan.
²⁶ Merck & Co., Inc., Boston, Massachusetts, USA.
²⁷ Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom.
²⁸ Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
²⁹ Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³⁰ The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³¹ Department of Medicine, Divisions of Hematology and Medical Oncology, University of Washington School of Medicine, Seattle, Washington, USA.
³² TwinStrand Biosciences Inc., Seattle, Washington, USA.
³³ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³⁴ Kymera Therapeutics, Watertown, Massachusetts, USA.

PMID: 39049734
DOI: 10.1089/hum.2024.033

Abstract

Regulators and industry are actively seeking improvements and alternatives to current models and approaches to evaluate potential carcinogenicity of gene therapies (GTs). A meeting of invited experts was organized by NC3Rs/UKEMS (London, March 2023) to discuss this topic. This article describes the consensus reached among delegates on the definition of vector genotoxicity, sources of uncertainty, suitable toxicological endpoints for genotoxic assessment of GTs, and future research needs. The collected recommendations should inform the further development of regulatory guidelines for the nonclinical toxicological assessment of GT products.

Keywords: carcinogenicity; gene therapy vectors; genotoxicity; insertional oncogenesis; nonclinical safety.

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Improving the Assessment of Risk Factors Relevant to Potential Carcinogenicity of Gene Therapies: A Consensus Article

Affiliations

Improving the Assessment of Risk Factors Relevant to Potential Carcinogenicity of Gene Therapies: A Consensus Article

Authors

Affiliations

Abstract

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MeSH terms

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

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