Targeting the TNFR2 oncogene on tumor cells and tregs of the tumor microenvironment via dominant TNFR2 antagonism.

106 Background: A major barrier to cancer immunotherapy is lack of selective inhibitors of the regulatory T cells (Tregs) of the cancer microenvironment and methods to directly kill tumors through novel surface oncogenes. Tumor necrosis factor receptor 2 (TNFR2) is a target protein with restricted expression on the most potent Tregs of the tumor infiltrate and newly identified as a broadly expressed oncogene on human tumors. Methods: We characterized the effect of TNFR2 antibody antagonists via TNFR2 in human samples from ovarian ascites compared to healthy controls. Results: TNFR2 antagonists potently inhibited Treg proliferation with exponential potency and selectivity for tumor microenvironment Tregs. Furthermore, common ovarian cancer cell lines such as OVCAR3 expressed the TNFR2 oncogene and were rapidly and completely killed by TNFR2 antagonistic antibodies. TNFR2 antagonistic antibodies were dominant because they succeeded even in the presence of TNF agonism. Remarkably, these antibodies worked as well in killing Treg cells as F(ab’)2 fragments, but not as well as Fc fragments. TNFF2 antagonists were not dependent on ADCC mechanisms for activity. Conclusions: Dominant TNFR2 antagonistic antibodies demonstrate tumor-specific Treg depletion. Blocking TNFR2 signaling with antagonist antibodies also creates a novel tool to possibly eliminate tumors expressing the TNFR2 oncogene and to more potently suppress Tregs of the tumor microenvironment.