Immunotherapy with Low-Dose Interleukin-2 and Interferon-γ in a Murine Tumor Model

The aim of this study was to evaluate the therapeutic efficacy of locally administered low-dose interleukin-2 (IL-2) alone or together with interferon-γ (IFN-γ) in a herpes simplex virus type 2-transformed murine (H238) fibrosarcoma model. In vitro incubation showed that IL-2, but not IFN-γ, had a significant inhibitory effect on DNA synthesis in H238 cells. In vivo experiments were performed with BALB/c mice to determine the optimal time of treatment with each cytokine after subcutaneous (sc) tumor implantation. The greatest antitumor effect with IL-2 (1 X 10⁵ total international units, sc) was noted when treatment was administered during the first week after tumor injection, whereas with IFN-γ (500 total units, intraperitoneally) treatment during the second week proved best. Combination of the two agents produced complete tumor regression in 44.4% of mice; regression with single-modality treatment was 0-11%. The presence of H238 tumor induced splenomegaly and enhanced the oxidative burst capacity of phagocytes. Peripheral blood leukocyte counts were low in tumor-bearing groups, regardless of treatment. IL-2 and IFN-γ were nondetectable in the plasma of tumor-bearing or control mice; however, total TGF-β₁ was 248% higher with IL-2 treatment compared with tumor-bearing nontreated controls. These results show that IL-2 and IFN-γ can significantly inhibit the growth of highly aggressive H238 tumors and support further investigations with these agents.