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 evaluate the toxicity and the clinical and immunologic effects of this cytokine combination. Thirty-nine eligible patients with refractory malignancy were treated at eight different dose levels (1A to 3B): 1-3 of rIL-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 toxicity of these two cytokines was moderate and was comparable with that seen with rIL-2 alone. The maximal tolerated dose (MTD) of the combination was not reached because of lack of sufficient rHuIL-4 but is at least 48.0 x 10(6) IU/m(2) of rIL-2 and 120 mu g/m(2) of rHuIL-4. Two patients with melanoma had partial responses. The immunologic effects included increases in absolute lymphocyte numbers, and the CD3- /CD56+/ CD2+, total CD56+, CD8+, and CD16c+ lymphocyte subsets with increasing rIL-2 dose levels, but not with rHuIL-4. This increase in natural killer (NK) cells in the peripheral blood was accompanied by an increase over baseline in NK lytic activity against K562 targets; however, concomitant increases in lymphokine-activated killer (LAK) activity (Daudi targets) were not seen. The CD3+, CD4+, and CD3+/CD25+/HLA-Dr+ T-cell subsets also increased, and these increases were related to both increasing rIL-2 and rRuIL-4 doses. Finally, in four of six patients, serial tumor biopsies demonstrated increases in major histocompatibility complex (MHC) class I or II antigen expression on tumor cells or increasing T-cell infiltrates during cytokine therapy or both. This trial demonstrated that rIL-2 and rHuIL-4 can be administered simultaneously with acceptable toxicity. The immunologic findings demonstrated the expected rIL-2-associated increases of CD56+ and CD16c+ lymphocytes and NK activity, and interestingly, no development of LAK activity. These findings suggest regulatory effects of rHuIL-4 on rIL-2-related effects in vivo.
Olencki
T
T
Experimental Therapeutics Program, The Cleveland Clinic Cancer Center, Ohio, USA.
Finke
J
J
Tubbs
R
R
Tuason
L
L
Greene
T
T
McLain
D
D
Swanson
S J
SJ
Herzog
P
P
Stanley
J
J
Edinger
M
M
Budd
G T
GT
Bukowski
R M
RM
D000276:Adjuvants, Immunologic / Q000009:adverse effects*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000473:pathology / Q000628:therapy; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016233:Immunotherapy, Active / Q000009:adverse effects; D007376:Interleukin-2 / Q000009:adverse effects*; D015847:Interleukin-4 / Q000009:adverse effects*; D007680:Kidney Neoplasms / Q000097:blood / Q000473:pathology / Q000628:therapy; D008297:Male; D008545:Melanoma / Q000097:blood / Q000473:pathology / Q000628:therapy; D008875:Middle Aged; D011994:Recombinant Proteins / Q000009:adverse effects; D012878:Skin Neoplasms / Q000097:blood / Q000473:pathology / Q000628:therapy; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D007376:Interleukin-2; D011994:Recombinant Proteins; D015847:Interleukin-4