EVALUATION OF NATURAL-KILLER-CELL EXPANSION AND ACTIVATION IN-VIVO WITH DAILY SUBCUTANEOUS LOW-DOSE INTERLEUKIN-2 PLUS PERIODIC INTERMEDIATE-DOSE PULSING

Natural killer (NK) cells may be expanded in vivo with a prolonged cou rse of daily subcutaneous interleukin-2 (IL-2). However, cellular acti vation requires higher concentrations of IL-2 than are achieved with l ow-dose therapy. The objective of the current trial was to determine t he toxicity and immunological effects of periodic subcutaneous interme diate-dose IL-2 pulses in patients receiving daily low-dose therapy. A group of 19 patients were treated with daily subcutaneous low-dose IL -2 at 1.25x10(6) International Units (1.25 MIU) m(-2) day(-1). After 4 -6 weeks, patients received escalating 3-day intermediate-dose IL-2 pu lses administered as single daily subcutaneous injections, repeated at 2-week intervals. The maximum tolerated pulse dose was 15 MIU m-2 day (-1), with transient hypotension, fatigue, and nausea/vomiting dose-li miting. Subcutaneous IL-2 resulted in in vivo expansion of CD56(+) NK cells (796 +/- 210%) and CD56(bright) natural killer (NK) cells (3247 +/- 1382%). Expanded NK cells coexpressed CD16, and showed lymphokine- activated killer activity and antibody-dependent cellular cytotoxicity in vitro. Intermediate-dose pulsing resulted in serum IL-2 concentrat ions above 100 pM. Cellular activation was suggested by rapid marginat ion of NK cells following pulsing, coincident with peak IL-2 levels, w ith return to baseline by 24 h. In addition, interferon gamma producti on in response to lipopolysaccharide was augmented. Subcutaneous daily low-dose IL-2 with intermediate-dose pulsing is a well-tolerated outp atient regimen that results in in vivo expansion and potential activat ion of NK cells, with possible application in the treatment of maligna ncy and immunodeficiency.