No abstract

Experimental work in murine models has shown that, during the development of tumors, prostaglandin E2 produced by host macrophages inactivates natural killer cells and suppresses lymphokine-activated killer (LAK) cell development. Chronic indomethacin therapy when combined with interleukin-2 (IL-2) can totally eradicate experimental lung metastases in these models. A phase II trial was performed to study the clinical efficacy of chronic indomethacin and intermittent IL-2 therapy in patients with advanced renal cell carcinoma. Patients were placed on indomethacin and ranitidine orally at least one week prior to commencing therapy with IL-2. IL-2 was given by continuous infusion for three courses, each consisting of 5 days of treatment with 6 days of rest. Initial dose of IL-2 was 18.0 x 10(6) IU/m2/day for the first course with escalation to 27.0 x 10(6) IU/m2/day for the second and 36.0 x 10(6) IU/m2/day for the third course, if toxicity allowed. Patients were admitted to a general oncology ward for therapy with IL-2, and vasopressor agents were not used. Thirty-two patients were eligible, with 7 patients withdrawing early from the study. Twenty-five patients went on to receive at least one course of IL-2. Two complete and three partial responses were seen for an objective response rate of 5/25 (20%) for eligible and treated patients or 5/32 (16%) for all patients entered onto the study, regardless of treatment status. The response rate to this regimen is comparable with other high dose IL-2 regimens in renal cell carcinoma, including those employing adoptive therapy with lymphokine-activated killer cells.

Previous clinical studies have demonstrated a dose-response relationship between enhancement of certain immune parameters and interleukin-2 (IL-2) dose in trials with low dosages of the cytokine. This has not been demonstrated for high-dose (greater than 18 x 10(6) IU/m2 per day) IL-2. We completed phase II trials of sustained administration of indomethacin and ranitidine with IL-2 given as a continuous infusion over 5 days for three courses. Peripheral blood mononuclear cells, both fresh and cultured in vitro with IL-2 or IL-2 and indomethacin, were tested for tumoricidal function against K562 and Daudi targets; these results were then correlated with actual delivered dose and mean infusion rate per course. Similar correlations were calculated between delivered dose or infusion rate and absolute and proportional counts of lymphocyte subsets as determined by flow cytometry. No enhancement of in vitro tumoricidal function with either increasing delivered dose or increasing infusion rate was seen. No consistent pattern of correlation was found between the absolute counts of lymphocyte subsets after each course of IL-2 with delivered dose or infusion rate. The percent rise in absolute counts of selected T- and NK-cell subsets at the end of course 1 compared with baseline values correlated positively with infusion rate; however, a similar correlated between the infusion rate and an increase in lymphocyte tumoricidal function was lacking. Little evidence was found for improved tumoricidal function of mononuclear cells or consistent enhancement of lymphocyte subset counts in patients able to tolerate doses of IL-2 beyond 18 x 10(6) IU/m2 per day in a 5-day continuous infusion schedule.

No abstract

Previous clinical studies have demonstrated a dose-response relationship between enhancement of certain immune parameters and interleukin-2 (IL-2) dose in trials with low dosages of the cytokine. This has not been demonstrated for high-dose (greater than 18 x 10(6) IU/m2 per day) IL-2. We completed phase II trials of sustained administration of indomethacin and ranitidine with IL-2 given as a continuous infusion over 5 days for three courses. Peripheral blood mononuclear cells, both fresh and cultured in vitro with IL-2 or IL-2 and indomethacin, were tested for tumoricidal function against K562 and Daudi targets; these results were then correlated with actual delivered dose and mean infusion rate per course. Similar correlations were calculated between delivered dose or infusion rate and absolute and proportional counts of lymphocyte subsets as determined by flow cytometry. No enhancement of in vitro tumoricidal function with either increasing delivered dose or increasing infusion rate was seen. No consistent pattern of correlation was found between the absolute counts of lymphocyte subsets after each course of IL-2 with delivered dose or infusion rate. The percent rise in absolute counts of selected T- and NK-cell subsets at the end of course 1 compared with baseline values correlated positively with infusion rate; however, a similar correlated between the infusion rate and an increase in lymphocyte tumoricidal function was lacking. Little evidence was found for improved tumoricidal function of mononuclear cells or consistent enhancement of lymphocyte subset counts in patients able to tolerate doses of IL-2 beyond 18 x 10(6) IU/m2 per day in a 5-day continuous infusion schedule.