Neoadjuvant interleukin-12 immunogene therapy protects against cancer recurrence after liver resection in an animal model

• Published in: Annals of surgery 2000-05, Vol.231 (5), p.762-771
• Main Authors: Jarnagin, W R, Delman, K, Kooby, D, Mastorides, S, Zager, J, Brennan, M F, Blumgart, L H, Federoff, H, Fong, Y
• Format: Article
• Language: English
• Subjects: Animals; beta-Galactosidase - metabolism; Genetic Therapy; Genetic Vectors; Hepatectomy; Interleukin-12 - genetics; Interleukin-12 - therapeutic use; Liver Neoplasms, Experimental - surgery; Liver Neoplasms, Experimental - therapy; Male; Neoplasm Recurrence, Local - prevention & control; Rats; Rats, Inbred BUF; Scientific Papers; Simplexvirus
• ISSN: 0003-4932; 1528-1140
• DOI: 10.1097/00000658-200005000-00017

To evaluate the neoadjuvant use of a herpes simplex viral (HSV) amplicon vector expressing the murine interleukin-12 (IL-12) gene. Surgery is the most effective therapy for hepatic malignancy. Recurrences, which are common, most often occur in the remnant liver and are due partly to growth of residual microscopic disease in the setting of postoperative host cellular immune dysfunction. The authors hypothesized that engineering tumors to secrete IL-12 in vivo would elicit an immune response directed at residual tumor and would reduce the incidence of recurrence after resection. Solitary hepatomas were established in Buffalo rat livers and directly injected with 106 particles of HSV carrying the gene for IL-12, lacZ (beta-galactosidase) or with saline. One week after injection, the animals were challenged with an intraportal injection of 106 tumor cells, with subsequent resection of the hepatic lobe containing the previously established macroscopic tumor nodule, recreating the clinical scenario of residual microscopic cancer. Hepatoma cells transfected with HSV-IL-12 produced high levels of IL-12 in vitro and in vivo. A significant local immune response developed, as evidenced by a progressive increase in the number of CD4(+) and CD8(+) lymphocytes in the tumor. Treatment of established hepatomas with HSV-IL-12 protected against growth of microscopic residual cancer after hepatic resection. Sixty-four percent of the animals treated with HSV-IL-12 had zero or one tumors compared with 30% of HSVlac-treated and 24% of saline-treated animals. This neoadjuvant immune strategy may prove useful in reducing the incidence of cancer recurrence after hepatic resection.