Serum cytokine levels in cancer patients treated with different schedules of ultra-low-dose interleukin-2.
Interleukin-2 (IL-2) induces secondary cytokines in vivo that may mediate antitumor effects as well as toxicity. The course and quantity of this in vivo reaction may depend on scheduling of IL-2 due to changes in responsiveness of the respective producer cells. This was evaluated in a phase-Ib study with ultra-low-dose IL-2 at 0.9 and 4.5 MIU/m2 administered once daily subcutaneously either once weekly (4 doses, stratum I), three times a week every other day (9 doses, stratum II), or five times a week every other week (10 doses, stratum III). Twenty-eight patients with advanced cancer were randomly assigned to the six treatment groups. Serum levels of IL-2, secondary cytokines, and soluble receptors were significantly increased after a single dose of 0.9 MIU/m2 s.c. demonstrating systemic efficacy. Baseline levels and native responsiveness were recovered after a 1-week treatment-free interval in stratum I patients with the exception of sCD8 that was still increased although readily inducible at that time. Stratum II patients exhibited a prolonged and possibly continuous elevation of all serum parameters studied. Values did not increase beyond the 2nd week of therapy and even decreased with respect to sCD8 and neopterin. A sequential mode of administration (stratum III) may obviate some of these adaptive mechanisms as evidenced from a progressive increase of neopterin and sCD8 levels after the second treatment cycle, although induction of sTNFRI was saturable under these conditions. Thus, scheduling of IL-2 profoundly affects in vivo responses as evidenced from cytokine and soluble receptor serum levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Lindemann
A
A
Department Medicine I, University of Freiburg, Germany.
Brossart
P
P
Höffken
K
K
Flasshove
M
M
Voliotis
D
D
Diehl
V
V
Kulmburg
P
P
Wagner
H
H
Mertelsmann
R
R
D000328:Adult; D000368:Aged; D016207:Cytokines / Q000097:blood*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D015375:Receptors, Interleukin-2 / Q000032:analysis; D011994:Recombinant Proteins / Q000008:administration & dosage
D016207:Cytokines; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins