Introduction: Tumor necrosis factor receptor 2 (TNFR2, or TNFRSF1B) is a lymphoid marker of the most potent regulatory T-cell (Treg) subtype and a commonly expressed oncogene in human tumors. TNFR2 Tregs are also enriched in the tumor microenvironment. TNFR2 antagonistic antibodies have been developed to inhibit NFkB-driven growth through the TNFR2 receptor, showing both Treg and tumor inhibition with specificity for the tumor microenvironment (Sci Signaling 2017). A mouse surrogate, TY101, has been developed to assess efficacy in murine models of colon cancer. Methods: We designed monoclonal antibodies to target the TNFR2 oncogene and directly kill tumor cells in syngeneic murine models of colon cancer: CT26 and MC28. All studies were conducted by an independent third party (Champions Oncology). The primary endpoint was a reduction in tumor size. Results: In MC38 mice, the TNFR2 antagonist combined with anti-PD1 immunotherapy was more effective than placebo or immunotherapy alone in reducing mean tumor volume (P=0.004). In CT26 mice, the TNFR2 antagonist as a monotherapy was more effective compared to placebo or combination therapy with anti-PD1 (p<0.0001). Conclusions: The results of this study in syngeneic mice suggest that novel anti-TNFR2 antibodies have potential to be used either alone or in combination with immunotherapy as a treatment for colon cancer and should be studied in future trials.

Citation Format: Russell LaMontagne. TNFR2-targeted elimination of Tregs and tumor-residing T-cells in a murine colon cancer model [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A199.