IMMUNOMODULATORY EFFECTS OF INTERLEUKIN-2 AND INTERLEUKIN-4 IN PATIENTS WITH MALIGNANCY

A phase I trial of simultaneously administered recombinant interleukin -2 (rIL-2) and recombinant human IL-4 (rHuIL-4) was conducted to evalu ate the toxicity and the clinical and immunologic effects of this cyto kine combination. Thirty-nine eligible patients with refractory malign ancy were treated at eight different dose levels (1A to 3B): 1-3 of rI L-2 [3.0, 12.0, and 48.0 x 10(6) IU/m(2) i.v. three times weekly (TIW) ] and A-C of rHuIL-4 (40, 120, and 400 mu g/m(2) s.c. TIW). The toxici ty of these two cytokines was moderate and was comparable with that se en with rIL-2 alone. The maximal tolerated dose (MTD) of the combinati on was not reached because of lack of sufficient rHuIL-4 but is at les t 48.0 x 10(6) IU/m(2) of rIL-2 and 120 mu g/m(2) of rHuIL-4. Two pati ents with melanoma had partial responses. The immunologic effects incl uded increases in absolute lymphocyte numbers, and the CD3(-)/CD56(+)/ CD2(+), total CD56(+), CD8(+), and CD16c(+) lymphocyte subsets with in creasing rIL-2 dose levels, but not with rHuIL-4, This increase in nat ural killer (NK) cells in the peripheral blood was accompanied by an i ncrease over baseline in NK lytic activity against K562 targets; howev er, concomitant increases in lymphokine-activated killer (LAK) activit y (Daudi targets) were not seen. The CD3(+), CD4+, and CD3(+)/CD25(+)/ HLA-Dr(+) T-cell subsets also increased, and these increases were rela ted to both increasing rIL-2 and rHuIL-4 doses. Finally, in four of si x patients, serial tumor biopsies demonstrated increases in major hist ocompatibility complex (MHC) class I or II antigen expression on tumor cells or increasing T-cell infiltrates during cytokine therapy or bot h. This trial demonstrated that rIL-2 and rHuIL-4 can be administered simultaneously with acceptable toxicity. The immunologic findings demo nstrated the expected rIL-2-associated increases of CD56(+) and CD16c( +) lymphocytes and NK activity, and interestingly, no development of L AK activity. These findings suggest regulatory effects of rHuIL-4 on r IL-2-related effects in vivo.