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Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice

Gene Therapy volume 15, pages 1056–1066 (2008)Cite this article

Abstract

There is considerable concern regarding the transforming potential of retroviral vectors currently used for gene therapy, with evidence that retroviral integration can lead to leukemia in recipients of gene-modified stem cells. However, it is not clear whether retroviral-mediated transduction of T cells can lead to malignancy. We transduced mouse T cells with a Moloney murine retroviral gene construct and transferred them into congenic mice, which were preconditioned to enhance the engraftment of transferred T cells. Recipients were then observed long-term for evidence of cancer. Transferred T cells persisted in mice throughout life at levels up to 17% with gene copy numbers up to 5.89 × 105 per million splenocytes. Mice receiving gene-modified T cells developed tumors at a similar rate as control mice that did not receive T cells, and tumors in both groups of mice were of a similar range of histologies. Hematological malignancies comprised approximately 60% of cancers, and the remaining cancers consisted largely of carcinomas. Importantly, the incidence of lymphomas was similar in both groups of mice, and no lymphomas were found to be of donor T-cell origin. This study indicates that the use of retroviral vectors to transduce T cells does not lead to malignant transformation.

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Acknowledgements

This work was supported by grants from The National Health and Medical Research Council of Australia (NHMRC), The Cancer Council of Victoria, The Bob Parker Memorial Trust and the Peter MacCallum Cancer Centre Foundation. MK is supported by a Career Development Award from the National Breast Cancer Foundation and NHMRC. PD is supported by a Career Development Award from the NHMRC, and MS and JT are supported by Senior Principal Research Fellowships from the NHMRC. NH is supported by a C.J. Martin Fellowship from the NHMRC. We would like to acknowledge the help from Dr Dominic Wall for helpful discussions, and Barbara Przybylowski, Darlene Deo, Brenda Aisbett, Elena Takano and Naomi Peters (PMCC, Melbourne, Australia) for histochemical slide preparation and staining. We also thank Carol Van Puyenbroek and Shannon Griffiths (PMCC) for assistance with mice.

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Authors and Affiliations

  1. Cancer Immunology Research Program, Peter MacCallum Cancer Centre (PMCC), Melbourne, Victoria, Australia

    J A Westwood, N M Haynes, J A Trapani, P Mayura-Guru, M J Smyth, P K Darcy & M H Kershaw

  2. Department of Pathology, PMCC, Melbourne, Victoria, Australia

    W K Murray, M Trivett & S Fox

  3. Haematology and Immunology Translational Research Laboratory, PMCC, Melbourne, Victoria, Australia

    A Shin, P Neeson, H M Prince & D Ritchie

  4. Department of Pathology, Austin Hospital, Heidelberg, Victoria, Australia

    D P MacGregor

  5. Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia

    J A Trapani & M J Smyth

  6. Department of Hematology, PMCC, Melbourne, Victoria, Australia

    S Peinert, D Honemann, H M Prince & D Ritchie

  7. Department of Medicine, University of Wuerzburg, Germany

    D Honemann

  8. Ludwig Institute for Cancer Research, Heidelberg, Victoria, Australia

    A M Scott & F E Smyth

  9. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia

    P K Darcy & M H Kershaw

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  1. J A Westwood
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Correspondence to M H Kershaw.

Additional information

Authorship: JW designed and performed research, analyzed data and drafted manuscript. WM, DM and MT performed histological analysis. AS and PN designed and performed quantitative PCR. NH contributed to cell persistence studies. JT and PG provided input into design of experiments. SF contributed to data analysis. SP and DH contributed to experimental design and data interpretation. MP and DR collaborated on study design. AMS and FS provided important reagents. MS and PD contributed to study design and data interpretation. MK designed and directed research and drafted the report.

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Westwood, J., Murray, W., Trivett, M. et al. Absence of retroviral vector-mediated transformation of gene-modified T cells after long-term engraftment in mice. Gene Ther 15, 1056–1066 (2008). https://doi.org/10.1038/gt.2008.47

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