Adjuvant interleukin-12 gene therapy for the management of colorectal liver metastases.
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.
Laboratory of Biology and Therapeutic of Immune Diseases, University Pierre and Marie Curie, CNRS UMR7087, Pitié-Salpétrière Hospital, Paris, France.
Arnaud
A
Alves
Eric
E
Vibert
Stephane
S
Trajcevski
Sounkary
S
Solly
Monique
M
Fabre
Olivier
O
Soubrane
Cheng
C
Qian
Jesus
J
Prieto
David
D
Klatzmann
Yves
Y
Panis
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015179:Colorectal Neoplasms / Q000473:pathology*; D003131:Combined Modality Therapy; D015774:Ganciclovir / Q000627:therapeutic use; D015316:Genetic Therapy; D007150:Immunohistochemistry; D018664:Interleukin-12 / Q000235:genetics / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000556:secondary* / Q000628:therapy*; D051381:Rats; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D018664:Interleukin-12; D013937:Thymidine Kinase; D015774:Ganciclovir