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Adjuvant interleukin-12 gene therapy for the management of colorectal liver metastases

Cancer Gene Therapy volume 11, pages 782–789 (2004)Cite this article

Abstract

In humans, no efficient treatment exists not only against multifocal liver metastases (LM) but also against recurrent microscopic liver metastases within the liver remnant following curative liver resection. Furthermore, in nonmultifocal LM, partial liver resection could be performed, but in more than 50% of the patients, tumor recurrence within liver remnant is observed, partly due to the growth of dormant cancer cells in the setting of postoperative host immune dysfunction. We investigated the therapeutic potential of interleukin-12 (IL-12) immuno-gene therapies in these experimental models under total vascular exclusion (TVE) of the liver. In rats with multiple LM of DHDK12 colon cancer cells, we observed a significant reduction in tumor volume after retroviral-mediated gene transfer of either herpes simplex virus thymidine kinase (HSV1-TK) and ganciclovir (GCV) administration, or IL-12. Combined treatment with HSV1-TK/GCV and IL-12 resulted in improved tumor volume reduction and even survival. In rats with recurrent microscopic DHDK12 LM established after partial liver resection, we observed significantly decreased recurrent tumor volumes and increased survival after retroviral-mediated IL-12 gene transfer. In both settings, immunohistological analysis revealed that IL-12 immuno-gene therapy was accompanied by an infiltration of CD8+ T lymphocytes within the tumors. Altogether, our results suggest that IL-12 adjuvant gene therapy could improve the management of patients with either resectable or unresectable LM.

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Acknowledgements

This work was supported by grants from the Assistance Publique des Hôpitaux de Paris (AP-HP), the Comité de Paris de la Ligue Nationale contre le Cancer (LNCC), the Association de Recherche contre le Cancer (ARC), the Laboratoire Aventis, the Académie Nationale de Médecine, the Fondation de l'Avenir, the Association Française contre les Myopathies (AFM), and the EU grant QLK3-CT-1999-00364.

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Authors and Affiliations

  1. Laboratory of Biology and Therapeutic of Immune Diseases, University Pierre and Marie Curie, CNRS UMR7087, Pitié-Salpétrière Hospital, Paris, France

    Arnaud Alves, Eric Vibert, Stephane Trajcevski, Sounkary Solly & David Klatzmann

  2. Laboratory of Surgical Research, Faculty of Medicine Cochin, Port Royal, Paris, France

    Arnaud Alves, Eric Vibert, Olivier Soubrane & Yves Panis

  3. Laboratory of Anatomic Diseases, Kremlin-Bicêtre Hospital, le Kremlin Bicêtre, France

    Monique Fabre

  4. Division of Hepatology and Gene Therapy, Faculty of Medicine, FIMA, University of Navarra, Pamplona, Spain

    Cheng Qian & Jesus Prieto

  5. Division of digestive Surgery, Lariboisière Hospital, AP-HP, Paris, France

    Yves Panis

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  1. Arnaud Alves
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Correspondence to Yves Panis.

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Alves, A., Vibert, E., Trajcevski, S. et al. Adjuvant interleukin-12 gene therapy for the management of colorectal liver metastases. Cancer Gene Ther 11, 782–789 (2004). https://doi.org/10.1038/sj.cgt.7700760

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