EFFECTS OF ANTI-TRANSFORMING GROWTH-FACTOR-BETA ANTIBODY AND INTERLEUKIN-2 IN TUMOR-BEARING MICE

In previous studies we found that the immunosuppression seen in mice b earing Herpes virus type 2-transformed (H238) fibrosarcoma was likely to be due to tumor-derived transforming growth factor-beta (TGF-beta). In vitro experiments showed that interleukin-2 (IL-2) and antibodies against TGF-beta could significantly counteract TGF-beta-induced depre ssion in lymphocytes. The present study was performed to determine if the administration of polyclonal anti-TGF-beta antibody and recombinan t IL-Z alone or in combination, could inhibit H238 tumor progression i n vivo and to investigate possible mechanisms of action. The tumor cel ls were injected sc. at 1 x 10(6) cells/mouse and treatments were give n 1-10 days post-injection. In phase I, a total of 25,000 units of IL- 2 (5,000 units/injection) and/or 900 ng of anti-TGF-beta (100 ng/injec tion) were administered i.p. per animal. Phase II was conducted simila rly, except that each mouse received a total of 127,500 units of IL-2, either with or without the same amount of antibody. No treatment-rela ted toxicity was noted Tumor volumes were monitored for 16-18 days aft er tumor implantation. The H238 tumors in treated mice from both both phases grew as rapidly as, or significantly faster than, in untreated controls. Significant enhancement of tumor growth was found in the gro ups given IL-2 as a single agent, regardless of total dose. The combin ation of the higher IL-2 dose with anti-TGF-beta resulted in more rapi d tumor progression than in animals given the antibody alone. Relative spleen weights, peripheral blood leukocyte counts, and the chemilumin escent oxidative burst of phagocytes were significantly elevated in al l tumor-bearing mice, whereas T cell response to mitogenic stimulation was depressed However, the oxidative burst capacity of spleen (but no t blood) cells and natural killer cell cytotoxicity were markedly lowe r in the treated groups compared to nontreated tumor-bearing controls. In contrast, plasma levels of tumor necrosis factor-alpha and IL-2 we re substantially higher in the group given both modalities (phase II) compared to the other treated groups. These findings show that anti-TG F-beta antibody, both with and without low-dose IL-2 regimens, can be safely administered in vivo. However, tumor growth was not delayed by the treatment protocols used The induction of hyporesponsiveness in ce rtain cell types may account, at least partly, for the enhancement see n in tumor progression.