Interleukin-18 is a potent cytokine expressed early in the immune response following cleavage in activated composes. We have investigated the in vivo antitumor effects of intratumoral (i.t.) administration of an adenoviral vector expressing biologically active murine interleukin (IL)-18 (Ad.PTH.IL-18). Substantial antitumor effects were observed when established MCA205 fibrosarcoma was treated in syngeneic immunocompetent mice with intratumoral injection of Ad.PTH.IL-18 (P = 0.0025 versus control vector treatment), generating potent cytotoxic T lymphocytes (CTLs) in culture. In contrast, the antitumor effect was absent, and cytotoxic activity was significantly less (P = 0.021) in gld mice (Fas ligand deficient). To enhance the in vivo antitumor activity of the treatment using Ad.PTH.IL-18, we co-injected immature DC and Ad.PTH.IL-18 i.t. into established, day 7 MCA205 fibrosarcoma and MC38 adenocarcinoma. Co-injection of both Ad.PTH.IL-18 and DC was associated with complete abrogation of injected tumors. Furthermore, the antitumor effects were also observed on distant tumors inoculated i.d. in the contralateral flank of the animal. The induced cytolytic activity was tumor-specific and MHC class I-restricted. As we have previously demonstrated in vitro (Tanaka F et al, Cancer Res 2000; 60: 4838-4844) and consistent with these findings in vivo, NK, T and dendritic cells coactivately mediate the IL-18 enhanced antitumor effect. This study suggests that the coactivate strategy could be used in the clinical setting to treat patients with cancer.
Bibliographical noteFunding Information:
This study was supported by Grant PO1 CA59371 (to MTL, PDR and HT), by The Uehara Memorial Foundation (Tokyo, Japan) Postdoctoral Research Fellowship (to FT), and by Grant-in Aid for Scientific Research (B: 12470237) from Japan Society for the Promotion of Science (to HT). We thank Susan F Schoonover (University of Pittsburgh) for her excellent technical assistance. We are grateful to Drs Andrea Gambotto, Tad-ashi Osaki (University of Pittsburgh) for generating adenoviral vector, and Dr Takuya Takayama, Motohiro Hirao (University of Pittsburgh) for helpful discussion. We also thank Professor Masaki Mori (Kyushu University, Japan) for helpful suggestions.
- Gene therapy
- Tumor immunity