Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2.

Abstract

We have previously demonstrated (1-4) that the incubation of human peripheral blood lymphocytes or murine splenocytes in the lymphokine, interleukin 2 (IL-2) 1, leads to the generation of cells capable of lysing fresh syngeneic or autologous tumors in short-term chromium-release assays. These lytic cells have been termed lymphokine-activated killer (LAK) cells, and they exhibit broad lytic specificity for a variety of fresh tumors, but they do not lyse fresh normal cells. Recombinant IL-2 produced in E. coli and purified to apparent homogeneity is highly effective in generating LAK cells from both human and murine lymphocytes (5). We have recently demonstrated (6, 7) that the intravenous injection of LAK cells in conjunction with recombinant IL-2 can mediate the regression of established pulmonary metastases from a variety of sarcomas, as well as from the B 16 melanoma.Because recombinant IL-2 is capable of efficiently generating LAK cells in vitro, and because the systemic administration of LAK cells has potent antitumor activities, we have studied the possible use of high-dose recombinant IL-2 administered directly to tumor-bearing mice, aiming to generate LAK cells in vivo and mediate tumor regression. In these studies, we have shown that the systemic administration of high doses of recombinant IL-2 leads to the generation of LAK cells in the spleens of recipient mice and mediates the regression of established pulmonary metastases and subcutaneous implants from a variety of tumors. Tumor regression appears to be mediated by endogenously activated lymphocytes, presumably LAK cells, present at the tumor site and in the organs of mice receiving high-dose recombinant IL-2. Materials and MethodsAnimals. Female C57BL/6 mice were obtained from the Small Animal Section, Veterinary Resources Branch, National Cancer Institute, Bethesda, MD, or from The Jackson Laboratory, Bar Harbor, ME. All mice were 12-16 wk old when used in experiments.Tumors. The MCA-105 and MCA-106 tumors were induced in our laboratory by 1 Abbreviations used in this paper: HBSS, Hank's balanced salt solution; IL-2, interleukin 2; LAK, lymphokine-activated killer cells; NK, natural killer cells. J. ExP. MED.

In vivo administration of interleukin 2 plus T cell-depleted syngeneic marrow prevents graft-versus-host disease mortality and permits alloengraftment.

“…Both NK and LAK cells have been shown to be activated by treatment with IL-2 in vivo (28)(29)(30)(31). Such cell populations in syngeneic marrow might suppress a GVH response better than similar populations in allogeneic marrow because oftheir ability to preferentially kill allogeneic and not syngeneic lymphoblasts (32), or to preferentially suppress responses directed against antigens shared by the suppressive population (9,23,27).…”

NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin 2-induced capillary leakage and reduces tumour growth in adenocarcinoma-bearing mice

“…In summary, L-NAME had anti-tumour effects in vivo, reduced the severity of IL-2-induced capillary leakage in some organs and did not compromise anti-tumour efficacy of IL-2 therapy. Thus, L-NAME could be a valuable adjunct to IL-2-based cancer therapy.Keywords: capillary leak syndrome; interleukin 2 cancer immunotherapy; mammary adenocarcinoma; nitric oxide; NG-nitro-L-arginine methyl ester Interleukin 2 (IL-2) therapy, alone or in combination with ex vivo-generated lymphokine-activated killer (LAK) cells, can cause tumour regression in mice (Rosenberg et al, 1985;Ettinghausen et al, 1988) and in man (Rosenberg, 1989;Fisher et al, 1988; Dutcher et al, 1989;Parkinson et al, 1990). Widespread clinical use of IL-2 has been limited by the low rate of complete remission and by severe toxicity Siegel and Puri, 1991).…”

Synergistic antitumor activity of tumor-infiltrating lymphocytes, interleukin 2, and local tumor irradiation. Studies on the mechanism of action.

“…IL-2 given either alone or in combination with the administration oflymphokineactivated killer (LAK)' cells has been shown to mediate the regression of established metastatic tumor both in mice and man (1)(2)(3). Furthermore, adoptive transfer of tumor-infiltrating lymphocytes (TIL) concomitant with the administration of IL-2 can mediate antitumor effects that are 50-100 times more potent in murine metastatic tumor models than those observed with LAK cells (4,5).…”