Immunotherapy with Low-dose Interleukin-2 and Antitransforming Growth Factor-β Antibody in a Murine Tumor Model

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Abstract
The purpose of the present study was to evaluate the therapeutic efficacy of low-dose interleukin-2 (IL-2) alone or together with antibody against transforming growth factor-β (TGF-β) in a Herpes simplex virus Type 2-transformed (H238) fibrosarcoma model. BALB/c mice were inoculated subcutaneously (s.c.) with 5 x 105 H238 tumor cells in one or both hind thighs and treated with IL-2, anti-TGF-β, or a combination of both agents. Nontreated tumor-bearing and normal animals served as controls. In the appropriate treatment groups, each mouse was given a total of 105 international units (i.u.) of IL-2 s.c. at one tumor implantation site and/or 1 μg of anti-TGF-β intraperitoneally (i.p.) over a period of 5 days beginning on the day of tumor cell implantation. No toxicity was noted during treatment. The slowest tumor growth was observed in mice with single tumors when treated with IL-2 or anti-TGF-β alone, whereas combination treatment resulted in growth similar to that of untreated controls. However, in animals with two tumors, the tumor injected with IL-2 grew more rapidly than the untreated one. Spleen cell responsiveness to mitogenic stimulation was generally depressed in tumor-bearing mice compared to normal controls, but some differences were noted with treatment. In contrast, tumor presence induced striking splenomegaly and enhanced the chemiluminescent oxidative burst of phagocytic cells in the spleen. In the groups with a single tumor, plasma TGF-β levels were similar to those of nontumor-bearing controls, however the concentrations were decreased in the animals with two tumors. These results show that IL-2 or anti-TGF-β can slow progression of H238 tumors under certain conditions. However, combination of the two modalities proved to be of no benefit.