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Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells

Gene Therapy volume 18, pages 1052–1062 (2011)Cite this article

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Abstract

We have previously described the oncolytic adenovirus, Ad(CgA-E1A-miR122), herein denoted Ad5(CgA-E1A-miR122) that selectively replicates in and kills neuroendocrine cells, including freshly isolated midgut carcinoid cells from liver metastases. Ad5(CgA-E1A-miR122) is based on human adenovirus serotype 5 (Ad5) and infects target cells by binding to the coxsackie-adenovirus receptor (CAR) and integrins on the cell surface. Some neuroendocrine tumor (NET) and neuroblastoma cells express low levels of CAR and are therefore poorly transduced by Ad5. However, they often express high levels of somatostatin receptors (SSTRs). Therefore, we introduced cyclic peptides, which contain four amino acids (FWKT) and mimic the binding site for SSTRs in the virus fiber knob. We show that FWKT-modified Ad5 binds to SSTR2 on NET cells and transduces midgut carcinoid cells from liver metastases about 3–4 times better than non-modified Ad5. Moreover, FWKT-modified Ad5 overcomes neutralization in an ex vivo human blood loop model to greater extent than Ad5, indicating that fiber knob modification may prolong the systemic circulation time. We conclude that modification of adenovirus with the FWKT motif may be beneficial for NET therapy.

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Acknowledgements

We would like to thank Linda Sandin for experimental help and Professor Ulf Landegren for sharing equipment. The Swedish Cancer Society (contracts 08-0582 and 10-0105), the Swedish Research Council (Grant K2008-68X-15270-04-3), Gunnar Nilsson's Cancer Foundation (Grant E50/08) and the Swedish Children Cancer Foundation (PROJ08/006) supported this work. ME is a recipient of the Swedish Cancer Society Senior Investigator Award.

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Authors and Affiliations

  1. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

    J Leja, D Yu, B Nilsson, A Zieba & M Essand

  2. Department of Radiology, Oncology and Radiation Sciences, Uppsala University, Uppsala, Sweden

    L Gedda

  3. Cancer Gene Therapy Group, Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland

    T Hakkarainen

  4. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden

    G Åkerström

  5. Department of Medical Sciences, Uppsala University, Uppsala, Sweden

    K Öberg & V Giandomenico

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Leja, J., Yu, D., Nilsson, B. et al. Oncolytic adenovirus modified with somatostatin motifs for selective infection of neuroendocrine tumor cells. Gene Ther 18, 1052–1062 (2011). https://doi.org/10.1038/gt.2011.54

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