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Leukocyte orchestration in blood and tumour tissue following interleukin-2 based immunotherapy in metastatic renal cell carcinoma

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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 α (IFN-α) 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 ζ expression, whereas blood lymphocytes showed almost normal levels of ζ 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, ζ-chain expression or cytotoxicity. In conclusion, the present regimen of outpatient low-dose subcutaneous IL-2 and IFN-α 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.

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Acknowledgements

We thank Dr Peter Hokland for providing access to the flow cytometer; Dr Theis Bacher for providing access to the gamma counter; Tom Nordfeld for running the Techmate automate immunohistochemistry machine; Karin Vestergaard for sectioning the biopsies; Anja Balmer and Bettina Grumsen for help with cytotoxicity and flow cytometry assays; Dr Ulrik Baandrup for help with eosinophil staining. Staff members at Department of Oncology are acknowledged for their careful management of the patients.

This study was supported by grants from the Danish Research Council, Radiumstationens Forskningsfond, Max and Inger Woerzner Foundation, Gerda and Aage Haench’s Foundation, Preben and Anna Simonsens Foundation, Agnes Niebuhr Anderssons Foundation, Kristian Kjaer Foundation, The Beckett Foundation, Hans and Nora Burchard’s Foundation, Agnes and Poul Friis Foundation, Erland Richard Frederiksen Foundation, Jacob Madsen and Olga Madsen Foundation, Johannes Fogh-Nielsen Foundation, Jens C. Christoffersen Foundation, the Danish Cancer Society (MH) and the Danish Medical Association Research Fund.

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Authors and Affiliations

  1. Department of Oncology, Aarhus University Hospital, Norrebrogade 44, 8000, Aarhus, Denmark

    Frede Donskov, Kirsten Fode & Hans von der Maase

  2. Institute of Medical Microbiology and Immunology, University of Aarhus, Aarhus, Denmark

    Frede Donskov, Karen Marie Bennedsgaard & Marianne Hokland

  3. Institute of Pathology, Aarhus University Hospital, Denmark

    Niels Marcussen

  4. Department of Radiology, Aahrus University Hospital, Aarhus, Denmark

    Rune Fisker & Hans Henrik Torp Madsen

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  1. Frede Donskov
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  2. Karen Marie Bennedsgaard
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Correspondence to Frede Donskov.

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Donskov, F., Bennedsgaard, K.M., Hokland, M. et al. Leukocyte orchestration in blood and tumour tissue following interleukin-2 based immunotherapy in metastatic renal cell carcinoma. Cancer Immunol Immunother 53, 729–739 (2004). https://doi.org/10.1007/s00262-004-0525-9

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