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Interleukin 12-based Immunotherapy Improves the Antitumor Effectiveness of a Low-Dose 5-Aza-2'-Deoxycitidine Treatment in L1210 Leukemia and B16F10 Melanoma Models in Mice¹

Katarzyna Kozar, Rafal Kamiski, Tomasz witaj, Tomasz Odak, Eugeniusz Machaj, Piotr J. Wysocki, Andrzej Mackiewicz, Witold Lasek, Marek Jakóbisiak and Jakub Gob²

Department of Immunology, Center of Biostructure, Medical University of Warsaw, 02-004 Warsaw [K. K., R. K., T. O., W. L., M. J., J. G.]; Department of Experimental Hematology, Maria Sklodowska-Curie Memorial Cancer Center, Institute of Oncology, 02-781 Warsaw [E. M.]; Department of Radiation Hematology, WIHiE, 04-363 Warsaw [T. O.]; Department of Cancer Immunology, Chair of Oncology, University School of Medical Sciences, GreatPoland Cancer Center, 61-866 Pozna, Poland [P. J. W., A. M.],

Purpose: Recent findings indicating that many genes related to cancer development are silenced by an aberrant DNA methylation suggest that inhibitors of this process may be effective cancer therapeutics. In this study we investigated the efficacy of low-dose 5-aza-2'-deoxycitydine (DAC), a methylation inhibitor, with interleukin (IL) 12, one of the most potent cytokines with antitumor activity.

Experimental Design: Mice inoculated with L1210 leukemia cells or with B16F10 melanoma cells were treated with 7 daily injections of low-dose DAC (0.2 mg/kg) and/or 7 daily doses of IL-12 (100 ng/dose). Scid/scid mice as well as monoclonal antibodies against CD4, CD8, and NK1.1 were used to investigate the mechanisms of the antitumor effects of the combination treatment. The activity of murine lymphocytes was measured with enzyme-linked immunospot and ⁵¹Cr release assays.

Results: Treatment with DAC or IL-12 given alone produced moderate antitumor effects. In both tumor models combined treatment resulted in potentiated antitumor effects and produced 70% long-term survivors among mice inoculated with L1210 cells. The antitumor efficacy of combined treatment was abrogated in scid/scid mice, and after depletion of CD4⁺ and CD8⁺ T cells. Mice inoculated with B16F10 melanoma cells had significantly delayed tumor growth after combined treatment with DAC and IL-12. Strong antitumor effect correlated with a significant activation of lymph node-derived CD8⁺ and CD4⁺ cells. Transient neutropenia was observed in mice under treatment of DAC alone, but remarkably this effect was not potentiated by IL-12.

Conclusions: This study provides the first evidence that antitumor effects of DAC can be strongly potentiated by IL-12 and could be beneficial in an effective low-dose-based antitumor therapy.

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