Increase in soluble interleukin-2 receptor and neopterin serum levels during immunotherapy of cancer with interleukin-2

Summary We have examined the efficacy, toxicity and host immunological response of two different dose schedules of interleukin2 (IL-2) given subcutaneously, daily for 3 months in patients with renal cell carcinoma (RCC) and neopterin concentration. Two patients with metastatic melanoma, one in each study, responded (11.8%); both received IL-2 alone. Observations of immunological parameters showed that treatment with subcutaneous IL-2 resulted in a significant rise in the percentage of PBLs bearing CD25, CD3/HLA-DR, CD56 and levels of IL-2 receptor and neopterin. The total white blood cell count (WBC) and total lymphocyte count rose significantly on day 18 compared with pretreatment levels. The addition of levamisole to either IL-2 schedule resulted in no significant changes in any immunological parameters. This study illustrates that prolonged subcutaneous IL-2 can be given safely in the outpatient setting. There was no evidence that levamisole acts as an immunomodulator in this study.

Section: Discussionsupporting

confidence: 82%

A randomised dose escalation study of subcutaneous interleukin 2 with and without levamisole in patients with metastatic renal cell carcinoma or malignant melanoma

Ahmed

Leonard²,

A’Hern³

et al. 1996

“…Although the bulk of i.v. bolus IL-2 administered to patients is cleared from the circulation within 30 min (Lotze et al, 1987), sIL-2R is induced at a much slower rate, reaching peak serum concentrations up to 2 weeks after prolonged IL-2 administration (Lissoni et al, 1991), and may take days to return to starting concentrations on cessation of IL-2 (Lotze et al, 1985). Our assessment of one patient on IL-2 therapy showed that, although the plasma contained a very high concentration of sIL-2R (30 504 U ml-'), suppression of growth of CTLL cells was similar to that achieved by plasma containing sIL-2R concentrations as low as 3000-6000 U ml-'.…”

Section: Resultsmentioning

confidence: 99%

Increased soluble interleukin-2 receptor concentration in plasma predicts a decreased cellular response to IL-2

Gooding

Riches²,

Dadian³

et al. 1995

Summary Interleukin 2 (IL-2) immunotherapy has met with limited success in the treatment of renal cell carcinoma (RCC) and malignant melanoma (MM). However, non-responders still account for up to 80% of those patients receiving IL-2. A high concentration of soluble IL-2 receptor (sIL-2R) is commonly found in the blood of such patients. We investigated the possibility that high sIL-2R concentration pretreatment may interfere with the bioavailability of IL-2. The mean concentration of sIL-2R in plasma from patients with MM, RCC and head and neck cancer was 3378 U ml-', 8778 U ml-' and 764 U ml-' respectively, compared with 1315 U ml-' in plasma from healthy volunteers. Inclusion of plasma from patients with RCC and MM patient plasma in cytotoxic T-lymphocyte leukaemic (CTLL) cell/IL-2 assays inhibited the ability of CTLL cells to respond to IL-2, and an inverse correlation was found between the concentration of sIL-2R and the growth response of CTLL cell to IL-2 (r = -0.86, P = 0.003). Plasma with soluble IL-2R concentrations greater than 3000 U ml-' produced a reduction in cell growth of more than 50% when included in CTLL IL-2 assays. The addition of increasing concentrations of IL-2 to cultures containing suppressive plasma failed to restore CTLL cell growth response to normal. Failure to saturate sIL-2R by exogenous IL-2 addition therefore suggests that another factor, initially present at a concentration similar to the sIL-2R concentration, is responsible for the observed effect. Determination of the suppressive effect of patient plasma as presented here may allow more effective IL-2 dosing schedules.

“…Several cytokines have been evaluated in association with IL-2 in an attempt to improve its clinical results, including interferons, tumour necrosis factor (TNF) and interleukin 6 (IL-6), without, however, any clear amplification of IL-2 efficacy (Atzpodien & Kirchner, 1990). The lack of efficacy of IL-2 alone in most solid tumour histotypes may depend at least in part on the concomitant generation of suppressive events, mainly mediated by macrophages (Lissoni et al, 1991). Moreover, immune responses depend not only on immune factors, but also on a great number of interactions between cytokines and neurohormones with immunomodulating effects, in particular the pineal indole melatonin (MLT) (Maestroni et al, 1986).…”

mentioning

confidence: 99%

A randomised study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma

Lissoni

Barni²,

Tancini³

et al. 1994

Summary Our previous experimental studies have shown that the best approach to increase the biological anti-tumour activity of interleukin 2 (IL-2) is not co-administration of another cytokine, but the association with immunomodulating neurohormones, in an attempt to reproduce the physiological links between psychoendocrine and immune systems, which play a fundamental role in the regulation of the immune responses. In particular, the association with the pineal neurohormone melatonin (MLT) has been shown to cause tumour regressions in neoplasms that are generally non-responsive to IL-2 alone. To confirm these preliminary results, a clinical trial was performed in locally advanced or metastatic patients with solid tumours other than renal cell cancer and melanoma. The study included 80 consecutive patients, who were randomised to be treated with IL-2 alone subcutaneously (3 million IU day-' at 8.00 p.m. 6 days a week for 4 weeks) or IL-2 plus MLT (40 mg day-' orally at 8.00 p.m. every day starting 7 days before IL-2). A complete response was obtained in 3/41 patients treated with IL-2 plus MLT and in none of the patients receiving IL-2 alone. A partial response was achieved in 8/41 patients treated with IL-2 plus MLT and in only 1/39 patients treated with IL-2 alone. Tumour objective regression rate was significantly higher in patients treated with IL-2 and MLT than in those receiving IL-2 alone (11/41 vs 1/39, P<0.001). The survival at 1 year was significantly higher in patients treated with IL-2 and MLT than in the IL-2 group (19/41 vs 6/39, P<0.05). Finally, the mean increase in lymphocyte and eosinophil number was significantly higher in the IL-2 plus MLT group than in patients treated with IL-2 alone; on the contrary, the mean increase in the specific marker of macrophage activation neopterin was significantly higher in patients treated with IL-2 alone. The treatment was well tolerated in both groups of patients. This study shows that the concomitant administration of the pineal hormone MLT may increase the efficacy of low-dose IL-2 subcutaneous therapy.