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/m(2) 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/m(2) 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. These data may be important for the design of IL-2 studies with respect to the induction of specific biological endpoints.