Targeted killing of TNFR2-expressing tumor cells and Tregs by TNFR2 antagonistic antibodies in advanced Sézary syndrome

Abstract

Sézary syndrome (SS) is a rare form of cutaneous T-cell lymphoma often refractory to treatment. SS is defined as adenopathy, erythroderma with high numbers of atypical T cells. This offers an opportunity for new interventions and perhaps antibody-based therapeutic by virtue of its high expression of the TNFR2 oncogene on the tumor cells and on T-regulatory cells (T_regs). Potent human-directed TNFR2 antagonistic antibodies have been created that preferentially target the TNFR2 oncogene and tumor-infiltrating TNFR2⁺ T_regs. Here we test the therapeutic potential of TNFR2 antagonists on freshly isolated lymphocytes from patients with Stage IVA SS and from healthy controls. SS patients were on a variety of end-stage multi-drug therapies. Baseline burden T_reg/T effector (T_eff) ratios and the responsiveness of tumor and infiltrating T_regs to TNFR2 antibody killing was studied. We show dose-escalating concentrations of a dominant TNFR2 antagonistic antibody killed TNFR2⁺ SS tumor cells and thus restored CD26^- subpopulations of lymphocyte cell numbers to normal. The abundant TNFR2⁺ T_regs of SS subjects are also killed with TNFR2 antagonism. Beneficial and rapid expansion of T_eff was observed. The combination of T_reg inhibition and T_eff expansion brought the high T_reg/T_eff ratio to normal. Our findings suggest a marked responsiveness of SS tumor cells and T_regs, to targeting with TNFR2 antagonistic antibodies. These results show TNFR2 antibodies are potent and efficacious in vitro.