1. ¹Laboratory of Biology and Therapeutic of Immune Diseases, University Pierre and Marie Curie, CNRS UMR7087, Pitié-Salpétrière Hospital, Paris, France
2. ²Laboratory of Surgical Research, Faculty of Medicine Cochin, Port Royal, Paris, France
3. ³Laboratory of Anatomic Diseases, Kremlin-Bicêtre Hospital, le Kremlin Bicêtre, France
4. ⁴Division of Hepatology and Gene Therapy, Faculty of Medicine, FIMA, University of Navarra, Pamplona, Spain
5. ⁵Division of digestive Surgery, Lariboisière Hospital, AP-HP, Paris, France

Correspondence: Professor Yves Panis, MD, PhD, Service de Chirurgie Digestive, Hôpital Lariboisiere, AP-HP, 2 rue Ambroise Pare, 75475 Paris cedex 10, France. E-mail: yves.panis@lrb.ap-hop-paris.fr

Received 17 February 2004; Published online 8 October 2004.

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.