YIA20-001: Targeting TGF-β in Ovarian Cancer Results in Decreased Tumor Burden and Improved T Cell Immune Response

Background: Increased transforming growth factor beta (TGF-β) is associated with poorer prognosis in advanced stage endometrial carcinoma (EOC). The immunosuppressive effects of this family of proteins promotes tumor progression and diminishes response to therapy. The objective of this study was to evaluate the effects of anti-TGF-β therapy in an immunocompetent ovarian cancer mouse model. Methods: ID8-p53-/- cells were injected intraperitoneally (I.P.) into C57BL/6 mice to establish our syngeneic ovarian cancer model. An intraperitoneal monoclonal antibody targeting all three TGF-β ligands was used as our anti-TGF-β therapy. Timing of anti-TGF-β therapy had three different treatment regimens. After 42 days of tumor challenge, ascites and omenta were harvested and weighed for tumor burden and changes in T cell response were measured using flow cytometry to calculate the CD8 to regulatory T cell (Tregs) ratio. Results: Treatment with anti-TGF-β therapy every other day beginning 7 days following tumor challenge resulted in decreased ascites volume (4.1mL vs 0.7mL; p < 0.001) and improvement in CD8: Treg ratio (0.37 vs 2.5; p = 0.02). However, there was no difference seen in the omental weights comparing treated and untreated mice. A single dose of anti-TGF-β therapy one day prior to 42 days of tumor challenge and with no additional therapy resulted in a similar reduction of ascites volume (2.7mL vs. 0.67mL p = 0.0024) and increased CD8: Tregs ratio (0.36 vs 1.49; p = 0.007), while also significantly reducing omental weight (114.9mg vs 93.4mg; p = 0.017). When the two regimens were combined – one dose prior to tumor cell injection followed by a dose every other day for 42 days, there was a significant reduction in ascites volume (2.24mL vs 0.69mL; p = 0.0025) and omental weight (124.9mg vs 84.3mg p = 0.004) and favorable changes in CD8: Tregs ratio (0.357 vs. 1.49; p = < 0.001). Furthermore, this regimen demonstrated prolonged overall survival, with median survival of 70 days in treated mice compared to 57.5 days in untreated mice. Conclusions: We show that inhibition of TGF-β with a monoclonal antibody results in reduced ascites production as well as favorable changes in the T cell profile. When treatment is introduced prior to tumor challenge, there is a reduction in tumor burden. These results suggest the potential for using anti-TGF-β therapy in the maintenance setting or in conjunction with immunotherapy in ovarian cancer patients.

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Corresponding Author: Rebecca Arend, MD
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