AdvIL-2

We studied the antitumor effects of recombinant human interleukin 2 (HuIL-2) in DBA/2 mice which harbor L5178Y lymphoma cells in a tumor-dormant state in the peritoneal cavity and in peritoneal cell (PC) cultures prepared from such mice. Intraperitoneal injection of 10,000 to 100,000 units of HuIL-2/day for 10 days eliminated tumor cells from 30-45% of the mice, whereas no mice became tumor-free in the phosphate-buffered saline-treated control group. In vitro, as little as 10 units/well HuIL-2 failed to stimulate cytotoxic activity in PC from normal mice. HuIL-2 directly stimulated antitumor cytotoxic activity in nonadherent but not in adherent PC cultures from tumor-dormant mice; however, treatment of whole PC from tumor-dormant mice with HuIL-2 resulted in the development of antitumor cytotoxic activity in the adherent PC population which were derived from such cultures. This suggests that the HuIL-2-treated nonadherent PC contributed to the cytotoxic activation of the adherent PC. Flow cytometric analysis of the PC from tumor-dormant mice revealed a polyclonal expansion of T-lymphocytes. Lyt-1+, Lyt-2+, and L3T4+ lymphocytes were all required for HuIL-2 to induce antitumor cytotoxic activity.

We reported previously that treatment of peritoneal cell (PC) cultures prepared from mice which harbor L5178Y lymphoma cells in a tumor-dormant state in their peritoneal cavity with interleukin 2 (HuIL-2) stimulated antitumor cytotoxic activity in both the nonadherent and adherent populations derived from such cultures. We report here that HuIL-2 induced the production of murine gamma interferon (MuIFN-gamma) in these PC cultures and required Lyt-1-, Lyt-2-, and L3T4-expressing lymphocytes to do so. HuIL-2 required and synergized with this induced MuIFN-gamma to stimulate cytotoxic activity in the nonadherent PC and the MuIFN-gamma itself stimulated cytotoxic activity in the adherent PC. Cyclosporin A prevented both the induction of MuIFN-gamma and the development of antitumor cytotoxic activity in HuIL-2-treated PC cultures. An addback of exogenous MuIFN-gamma to HuIL-2-cyclosporin A-treated PC cultures and to the nonadherent subpopulation of such cultures, at a concentration which itself produced no antitumor effect, permitted HuIL-2 to induce its antitumor effect. We previously reported that MuIFN-gamma requires the action of murine tumor necrosis factor (MuTNF) to induce cytotoxic activity in PC cultures from tumor-dormant mice. We report here that HuIL-2 also requires the action of (MuTNF) to stimulate antitumor cytotoxic activity in PC cultures from tumor-dormant mice. These results indicate that HuIL-2 induces MuIFN-gamma and requires and synergizes with this MuIFN-gamma and with (MuTNF) to stimulate antitumor cytotoxic activity in PC cultures from tumor-dormant mice.