title: Leukocyte orchestration in blood and tumour tissue following interleukin-2 based immunotherapy in metastatic renal cell carcinoma.
abstract: With the objective of evaluating leukocyte orchestration in situ, serial blood samples and tumour tissue core needle biopsies were obtained at baseline and repeated after 1 month of therapy, among 49 consecutive single-institution patients with metastatic renal cell carcinoma (mRCC). Patients were treated with outpatient low-dose subcutaneous interleukin 2 (IL-2) and interferon alpha (IFN-alpha) alone (n = 23) or in combination with histamine dihydrochloride (n = 26). Objective responses were achieved in ten of 49 patients (20%) with an overall median survival of 14 months and an estimated 1- to 4-year survival rate of 57, 35, 24 and 22%, respectively. Toxicity was mild to moderate with no treatment-related deaths. High numbers of blood monocytes and neutrophils were significantly correlated to short survival. By contrast, high numbers of intratumoural CD3+, CD4+, CD8+ and CD57+ lymphocytes were positively correlated to objective response and/or long-term survival. Intratumoural lymphocytes showed low zeta expression, whereas blood lymphocytes showed almost normal levels of zeta expression. Neutrophils, the most frequent peripheral blood leukocyte subset, were scarce within the tumour tissue. Intratumoural eosinophils were not observed. In progressing patients, both the absolute number and the relative composition of leukocyte subsets in blood and tumour tissue remained unaffected by cytokine therapy. However, in responding patients, cytokine therapy was followed by an absolute and relative increase in T cells in blood as well as tumour tissue, an absolute and relative reduction in neutrophils in peripheral blood and a relative reduction of intratumoural macrophages. Histamine did not influence levels of intratumoural or blood leukocyte numbers, zeta-chain expression or cytotoxicity. In conclusion, the present regimen of outpatient low-dose subcutaneous IL-2 and IFN-alpha in mRCC should attract interest based on response, survival and toxicity. In responding patients, cytokine therapy was followed by substantial changes in the blood and tumour tissue leukocyte composition, correlated to response and survival. No discernable differences in immunologic parameters studied could be detected between histamine- and nonhistamine-treated patients.
authors.affiliation: Institute of Medical Microbiology and Immunology, University of Aarhus, Denmark. fd@microbiology.au.dk
authors.forename: Frede
authors.initials: F
authors.lastname: Donskov
authors.forename: Karen Marie
authors.initials: KM
authors.lastname: Bennedsgaard
authors.forename: Marianne
authors.initials: M
authors.lastname: Hokland
authors.forename: Niels
authors.initials: N
authors.lastname: Marcussen
authors.forename: Rune
authors.initials: R
authors.lastname: Fisker
authors.forename: Hans Henrik Torp
authors.initials: HH
authors.lastname: Madsen
authors.forename: Kirsten
authors.initials: K
authors.lastname: Fode
authors.forename: Hans
authors.initials: H
authors.lastname: von der Maase
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D004359:Drug Therapy, Combination; D005260:Female; D006632:Histamine / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy; D016898:Interferon-alpha / Q000627:therapeutic use; D007376:Interleukin-2 / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D007694:Killer Cells, Natural / Q000276:immunology; D007962:Leukocytes / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D011446:Prospective Studies; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D016898:Interferon-alpha; D007376:Interleukin-2; D006632:Histamine