Abstract 1790: TNFR2-targeted elimination of Tregs and tumor-residing T cells in advanced cutaneous T cell lymphoma
Authors: Faustman Denise L. , Torrey Heather , Khodadoust Michael , Defusco Audrey , Baum Danielle , Rahbar Ziba , Kim Youn H. 
Published: August 2018

Abstract
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 (Sézary 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- Sézary 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&lt; 0.05), numbers of Teffs were depressed (CTCL vs Control, 3% vs 8%, p&lt; 0.05), and Treg/Teff ratios were abnormally elevated (CTCL vs Control, 8% vs 1%, p&lt; 0.05). Regardless of underlying therapy used in vivo, TNFR2 antagonism showed dose-responsive killing of the tumor cells within the CD26- fraction of peripheral CD4 T cells. TNFR2 antibody antagonism also showed specificity for tumor cells over CD26- cells from paired controls. In vivo treatment of CTCL subjects with an anti-proliferative agent such as methotrexate hindered TNFR2 antagonism driven killing, demonstrating the specificity of TNFR2 antagonism for rapidly proliferating cells. In dose response experiments in vitro, TNFR2 antagonism also had the desired dual effect of potent Treg killing combined with potent unleashing of Teff proliferation. Conclusions: TNFR2 can potentially be targeted in CTCL to directly stop the growth of tumor cells by antibody-induced cell death. TNFR2 antagonism may also provide the ability to eliminate the potent Tregs of the tumor microenvironment and unleash Teff proliferation.
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.