Recombinant interleukin-2 (rIL-2) with flavone acetic acid (FAA) in advanced malignant melanoma: immunological studies

Abstract

Summary Natural killer (NK) cell activity and lymphokine activated killer (LAK) cell cytotoxicity were measured in patients receiving recombinant interleukin 2 (rIL-2) and flavone acetic acid (FAA) for treatment of progressing metastatic melanoma. NK activity was increased in 23 of 26 patients and LAK activity induced in 13 of 26 patients. However, levels of cytotoxicity in the present study were not significantly greater than a previous study using rIL-2 alone. LAK cell precursors demonstrated by in vitro incubation of pretreatment lymphocytes with IL-2 and subsequent cytotoxicity were no different in the patients compared to normal controls. Analysis of cell surface phenotypes failed to reveal any significant changes in the cell populations examined, including IL-2R and Leu 19. Although five patients had tumour response, one being complete, there was no correlation with the immunological parameters examined.Several studies have shown that the administration of interleukin 2, either alone or in conjunction with broadly cytotoxic lymphokine activated killer cells (LAK) generated by in vitro co-culture with IL-2 have resulted in tumour regression in a range of established human tumours including melanoma (Rosenberg et al., 1987;Rosenberg, 1988;West et al., 1987; Hank et al., 1988). This combined adoptive immunotherapy is, however, expensive and labour intensive, and toxicity is severe when high doses of IL-2 are used. In our previous phase I/II clinical trial of intrasplenic and intravenous rIL-2 less toxicity was achieved and partial clinical responses were observed in 15% of patients with progressing advanced melanoma (Thatcher et al., 1989). These encouraging results stimulated interest in using rIL-2 in combination with other biological response modifiers or with chemotherapeutic drugs in the hope that better clinical responses could be achieved.Flavone acetic acid (FAA) is a synthetic flavonoid found to have an antitumour effect against a spectrum of murine solid tumours and to augment natural killer cell activity in spleen and other tissues in normal mice (Finlay et al., 1988;Zaharko et al., 1986;Ching & Baguley, 1987). This suggested that FAA may act as a biological response modifier as well as functioning as a chemotherapeutic drug. NK cells have been shown to be the major effector cell population contributing to the generation of LAK activity by rIL-2 (Itoh et al., 1985;Ferrini et al., 1987;Herberman et al., 1987 without local radiotherapy, although no patients had received anti-tumour treatment 4 weeks before entry into the study. Further clinical details from these patients are described elsewhere (Thatcher et al., 1990).Interleukin-2/flavone acetic acid administration Recombinant IL-2 (kindly supplied by Eurocetus BV, Amsterdam) was administered as described previously by Thatcher et al. (1989). Briefly, the initial dose (intrasplenic) was followed 4 h later by intravenous administration followed by three alternate day i.v. doses. A maximum of three such courses was given at 21-day intervals after the...