Modulation of B16 melanoma growth and metastasis by anti-transforming growth factor β antibody and interleukin-2

Earlier evidence suggests that transforming growth factor β (TGFβ) plays a significant role in tumor progression and metastasis. The most likely mechanism of the action of TGFβ is induction of immunosuppression in the host, allowing for unchecked tumor growth and metastasis. We attempted to test that hypothesis and to compare antitumor effects of anti-TGFβ antibody alone and in combination with interleukin-2 (IL-2). Six- to 8-week-old female C57B1-6 mice were induced with murine B16 melanoma by tail vein injection. Therapy was started 48 h after tumor injections. Monoclonal anti-TGFβ antibody (2G7) was administered intraperitoneally (i.p.) at 500 μg every other day, and IL-2 at 10,000 U i.p. twice daily, for 21 days. A threefold decrease in the number of lesions in the anti-TGFβ/IL-2 treatment group compared with the control group was observed, a highly significant statistical difference (p = 0.002). No statistically significant differences were seen between the control group and other studied groups (IL-2 alone, anti-TGFβ alone). Analysis of TGFβ levels in plasma by the TGFβ-1 Quantikine assay indicated normal levels in the control and IL-2 groups, and significantly diminished levels in the two groups that received TGFβ antibody. However, acid-ethanol extraction of plasma (to reverse antibody binding before assay) showed normal plasma TGFβ levels in all groups, suggesting that the antibody may alter the availability of TGFβ in vivo. Microscopic analysis of metastases revealed a decrease in the average size of lesions in the groups treated with IL-2. Thus, combination therapy using anti-TGFβ antibody and IL-2 may be a novel, less toxic approach to tumor immunotherapy.