DAILY SUBCUTANEOUS INJECTION OF LOW-DOSE INTERLEUKIN-2 EXPANDS NATURAL-KILLER-CELLS IN-VIVO WITHOUT SIGNIFICANT TOXICITY

We aimed to determine the toxicity and immunological effects of daily s.c. administered low-dose interleukin (IL) 2, Adult cancer patients r eceived a single daily s.c. injection of IL-2 as outpatients for 90 co nsecutive days, Cohorts of four to nine patients were treated at escal ating IL-2 dose levels until the maximum tolerated dose (MTD) was defi ned, Peripheral blood mononuclear cell phenotyping, IL-2 serum levels, and the presence of anti-IL-2 antibodies were investigated, Thirty-ei ght patients were treated at seven IL-2 dose levels ranging from 0.4 t o 1.75 million International Units (mIU)/m(2) daily, The MTD was 1.25 mIU/m(2), with constitutional side effects, vomiting, and hyperglycemi a dose limiting, Severe toxicity did not occur at or below the MTD, al though mild local skin reaction and mild constitutional side effects w ere common, Objective tumor regressions were not observed during this Phase I trial, Low-dose IL-2 resulted in natural killer (NK) cell (CD3 (-)CD56(+)) expansion at all dose levels, This effect was dose depende nt (P < 0.01), ranging from a 154 to 530% increase over baseline, Peak NK levels were achieved at 6-8 weeks and sustained through 12 weeks o f therapy, As predicted by in vitro studies of IL-2 receptor structure activity relationships, the subset of NK cells that constitutively ex press high-affinity IL-2 receptors (CD3(-)CD56(bright+)) showed more p rofound dose-dependent expansion, with increases ranging from 368 to 2 763% (P = 0.015), NK expansion occurred at peak IL-2 levels <10 pM (2. 3 IU/ml), Three patients developed nonneutralizing anti-IL-2 antibodie s, Thus, we concluded that selective expansion of NK cells may be achi eved in vivo with daily s.c. injections of low-dose IL-2 with minimal toxicity.