Abstract 1790: TNFR2-targeted elimination of Tregs and tumor-residing T cells in advanced cutaneous T cell lymphoma

Background: 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 recently 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). TNFR2 is a candidate oncogene in cutaneous T cell lymphoma (CTCL), with recurrent point mutations and gain of function alteration of TNFR2 resulting in abnormal expression of TNFR2 on CD4+CD26- tumor cells (Nat Genet 2015). Methods: We designed monoclonal antibodies to target the TNFR2 oncogene and directly kill human tumor cells in CTCL. TNFR2-directed monoclonal antibodies were screened for their ability to induce the death of leukemic cells in patients with Stage IV CTCL (Sezary syndrome) on a diversity of prior treatment regimens, as well as their ability to induce killing of tumor-associated Tregs and induce effector T cell (Teff) proliferation. Studies were performed in vitro on sorted CD4+CD26- Sezary cells or V-beta specific populations when a tumor was typed. Results: Baseline blood samples from patients with CTCL showed significant burdens of tumor cells within the CD26- subset of CD4 cells, in contrast to control blood cells. In CTCL subjects, numbers of Tregs (CD4+CD25hiFoxp3) were also elevated at baseline (CTCL vs Control, 11% vs 7%, p Citation Format: Denise L. Faustman, Heather Torrey, Michael Khodadoust, Audrey Defusco, Danielle Baum, Ziba Rahbar, Youn H. Kim. TNFR2-targeted elimination of Tregs and tumor-residing T cells in advanced cutaneous T cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1790.