IMMUNOMODULATORY EFFECTS OF ULTRA-LOW-DOSE INTERLEUKIN-2 IN CANCER-PATIENTS - A PHASE-IB STUDY

High-dose interleukin-(IL-2) has been broadly studied in tumour therap y, yet it may be inhibitory to T-cell-dependent immunity. Therefore im mune and tumour responses mediated by low-dose IL-2 were studied syste matically with respect to the feedback organisation of immune response s. IL-2 was administered once daily at three dose levels: 0.18, 0.9, 4 .5 MIU/M2 according to three different schedules requiring subcutaneou s (s.c.) injection once weekly (four doses, stratum I), thrice weekly every other day (nine doses, stratum II), or five times weekly every o ther week (ten doses, stratum III). A total of 46 patients with advanc ed cancer were randomly assigned to one of the nine treatment groups. Systemic effects were induced at doses as low as 0.18 MIU/M2 IL-2 s. c . as demonstrated from measurable IL-2 serum levels, induction of circ ulating IL-6, a transient lymphopenia, and stimulation of delayed-type hypersensitivity (DTH) responses of the skin. Analysis of the differe nt IL-2 schedules demonstrated (a) prolonged effects of once-weekly in jections on DTH responses, lymphocyte and eosinophil counts, and (b) m aximum increase of cosinophil counts and preferential expansion of act ivated NK cells with repeated injections every 48 h or 72 h (stratum I I), while sequential treatment according to stratum III was found to b e more potent in increasing the number of activated T cells. A tumour response was observed in 1/15 patients with renal cell carcinoma who e xperienced more than 50% tumour regression for 8 months; 12 patients h ad stable disease for 4 months (median). These data demonstrate prolon ged immunological effects of ultra-low doses of s. c. IL-2 despite its short half-life. Furthermore, scheduling of IL-2 was found to affect immune responsiveness specifically as demonstrated by the differential effects on natural killer and T cell populations.