Phase 1 clinical evaluation of recombinant interleukin-2.

The availability of large quantities of pure recombinant IL-2 has permitted clinical studies of its effects in patients with cancer. Based on the rapid half-life (3-5 minutes) and the need for prolonged exposure to IL-2 to maximally stimulate responsive cells we conducted a Phase 1 clinical trial designed to compare the clinical tolerance, immunologic effects and antitumor activity of IL-2 given by CI and daily BI for 7 consecutive days. The MTD of IL-2 based on completion of 7 days of treatment was found to be 3 X 10(6) U/m2/day for BI and 10(6) U/m2/day for CI. These results are approximately equivalent to those reported by others (Lotze, 1985 and Atkins, 1986), provided corrections are made for activity (2.3 Cetus IL-2 units = 1 BRMP IL-2 Unit). Although dose limiting toxicity was observed at the higher doses of IL-2 tested, these doses were tolerated for a shorter period of time (3-4 days) with striking immunologic effects (Sondel et al. 1987). As such, shorter treatment schedules utilizing higher doses of IL-2 warrant further investigation. The toxicity associated with the administration of IL-2 is considerable and clearly dose related. Of particular clinical importance is the fever, hypotension, fluid accumulation and decrease in PS. The etiology of these toxicities appears to be related to the release of endogenous cytokines following activation of the patient's immune system. It is also possible that the in vivo activation by IL-2 of cells mediating NRC may play some role in the toxicity associated with IL-2 (Sondel, 1986). It remains unclear whether immunosuppressive methods such as the use of cyclophosphamide or steroids will enable blockade of the immune mediated toxicity without also diminishing its therapeutic value. Further studies examining methods to control the severe toxicity associated with high doses of IL-2 are needed. The future role that IL-2 may play in treating cancer is unclear. Whether IL-2 alone can have significant antitumor activity may depend on factors such as tumor bulk, the patient's inherent ability to generate cytotoxic cells or the susceptibility of a particular malignancy. As such further studies will need to examine the importance of dose, timing, schedule, method of IL-2 administration as well as tumor burden in a wide variety of cancers.(ABSTRACT TRUNCATED AT 400 WORDS)