Clinical and immunomodulatory effects of repetitive 2-day cycles of high-dose continuous infusion IL-2.
High-dose interleukin-2 (IL-2) treatment has demonstrated promising antitumour activity in renal cell carcinoma (RCC) and malignant melanoma (MM) and has been shown to induce broad immunological effects. The optimal IL-2 dose and schedule, however, still remain to be defined. We studied a treatment protocol consisting of five repetitive cycles of high-dose recombinant (rh) IL-2 (24 x 10(6) U/m2/day) administered weekly on two consecutive days by continuous intravenous infusion. 17/19 were RCC patients, 2 of whom responded with a complete remission (CR) and 3 with a partial response (PR) (CR + PR: 29%; median response duration of 11.5+ months (range: 3-14 months)). IL-2 induced a pronounced increase of lymphocytes and pro-inflammatory cytokines IL-8, IL-5, gamma-IFN, TNF- alpha and TNF-beta (p < 0.05) that peaked in cycle 3. With subsequent therapy, serum levels of these cytokines, NK, T cells and eosinophils decreased, whereas serum IL-10 levels progressively increased with maximum levels achieved after the fifth week of treatment, suggesting that it may be involved in dampening the inflammatory response induced by IL-2. Absolute numbers of activated T cells and NK cells remained elevated as compared to baseline for at least 4 weeks after treatment cessation. Based on these observations, future scheduling of IL-2 will be done at 3 weekly 2-day cycles separated by a week 4 treatment-free interval in order to increase further the 29% objective response rate achieved in this study.
Engelhardt
M
M
Department of Internal Medicine I, University of Freiburg, Germany.
Wirth
K
K
Mertelsmann
R
R
Lindemann
A
A
Brennscheidt
U
U
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001772:Blood Cell Count; D002292:Carcinoma, Renal Cell / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000097:blood; D006801:Humans; D007262:Infusions, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D007694:Killer Cells, Natural; D016131:Lymphocyte Subsets / Q000187:drug effects; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D012074:Remission Induction; D016176:T-Lymphocyte Subsets / Q000187:drug effects
D000970:Antineoplastic Agents; D016207:Cytokines; D007376:Interleukin-2