Repetitive weekly cycles of interleukin-2. II. Clinical and immunologic effects of dose, schedule, and addition of indomethacin.
Clinical trials with high doses of interleukin 2 (IL-2) have shown antitumor responses, but many of the patients have experienced severe and occasionally life-threatening toxic effects. Preclinical studies indicate that modifications in IL-2 dose, route, and schedule can influence both immune activation and antitumor effects. This study evaluated the clinical tolerance to and immunologic modifications induced by four repetitive weekly cycles of IL-2, with two dose levels (1 X 10(6) and 3 X 10(6) U/m2 per day) of IL-2 and three different daily administration schedules [bolus, continuous, or combined (bolus and continuous)], with and without indomethacin treatment. Patients in all treatment groups experienced acceptable, non-life-threatening toxic effects and immune system stimulation characterized by rebound lymphocytosis with increased numbers of natural killer and lymphokine-activated killer cells and enhanced direct cytolytic function. These immune changes were significantly enhanced by the repetition of IL-2 cycles beyond the first week of therapy. At an IL-2 dose of 3 X 10(6) U/m2 per day, bolus IL-2 was less immunostimulatory than continuous-infusion IL-2. The combined regimen (with half of each daily dose given as a bolus and half as a 24-hr infusion) was as stimulatory as continuous-infusion IL-2 and also induced antitumor effects. Finally, the addition of indomethacin to this regimen did not significantly modify in vitro or in vivo immune response parameters but appeared to worsen the systemic toxic effects of renal dysfunction and capillary leakage. These results suggest that continuous or combined infusion of IL-2 at 3 X 10(6) U/m2 per day on this schedule should be considered for further testing in phase II trials or in combination with other therapeutic modalities.
Sosman
J A
JA
Department of Human Oncology, University of Wisconsin Medical School, Madison.
Kohler
P C
PC
Hank
J A
JA
Moore
K H
KH
Bechhofer
R
R
Storer
B
B
Sondel
P M
PM
D000328:Adult; D000368:Aged; D003602:Cytotoxicity, Immunologic; D004334:Drug Administration Schedule; D005260:Female; D005334:Fever / Q000209:etiology; D006801:Humans; D007022:Hypotension / Q000209:etiology; D007109:Immunity / Q000187:drug effects*; D007213:Indomethacin / Q000494:pharmacology*; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000188:drug therapy; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged
D007376:Interleukin-2; D007213:Indomethacin