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

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 þ 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.

Tumor Recurrence After Partial Hepatectomy for Liver Metastases in Rats: Prevention by In Vivo Injection of Irradiated Cancer Cells Expressing GMCSF and IL-12

“…We believed that this model might modify the host immune antitumoral response and is too far from the clinical situation. We recently developed another model with partial hepatectomy after intraportal injection of cancer cells within all of the lobes of the liver [14]. In the present study, we demonstrated that this model was not only feasible and reproducible, but also mimicked quite well what is observed in humans: no macroscopic tumors within the remnant liver at the time of partial hepatectomy but evidence of tumors 27 days later.…”

“…Not only a direct cytotoxic effect by HSV1-TK gene transfer and Ganciclovir treatment was noted but also an induction of activated T cells leading to an antitumoral efficiency, called "bystander effect" [5]. In a recent study, we showed in a model of nonresectable liver metastases that retroviral vectors expressing IL-12 gene significantly reduced tumor volume because the combination of IL-12 and HSV1-TK gene transfer was more effective than therapy with either of the two vectors alone [14]. However, in this study [14], as well as in other reports, because the rate of transfected cancer cells remains low after in vivo gene transfer, it could represent a limitation for either curative or preventive treatment in humans.…”

“…In a recent study, we showed in a model of nonresectable liver metastases that retroviral vectors expressing IL-12 gene significantly reduced tumor volume because the combination of IL-12 and HSV1-TK gene transfer was more effective than therapy with either of the two vectors alone [14]. However, in this study [14], as well as in other reports, because the rate of transfected cancer cells remains low after in vivo gene transfer, it could represent a limitation for either curative or preventive treatment in humans. Another solution is to use autologous cancer cells after in vitro transfection with therapeutic genes.…”

Cancer Electrogene Therapy with Interleukin-12

“…It has profound antitumor efficacy that was demonstrated on a variety of different types of tumors and metastases in preclinical as well as clinical studies. In recent years, several excellent reviews describing the activities of IL-12, the preclinical and clinical use of recombi-nant IL-12 and gene therapy with IL-12 have been published [1,8,11,45,56,57]. On the other hand, 10 years have passed since the first paper on combination of plasmid DNA encoding for IL-12 injected intramuscularly with electroporation was published [39].…”

“…The delivery systems for IL-12 gene therapy are various and include transfer of naked plasmid DNA alone [27,28], adenoviral [29][30][31][32][33] or other viral vectors [34][35][36], as well as gene gun [37,38], electroporation [39][40][41][42] and other non-viral vectors [43,44]. Clinical studies in human and also in veterinary oncology were initiated and the first results showed that IL-12 gene therapy is a safe treatment with some beneficial clinical effect [28,[45][46][47][48][49][50][51][52][53][54][55].…”