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

Sezary 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-re(gs)). Potent human-directed TNFR2 antagonistic antibodies have been created that preferentially target the TNFR2 oncogene and tumor-infiltrating TNFR2(+) T-re(gs). 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-re(gs) 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-re(gs)/T-eff ratio to normal. Our findings suggest a marked responsiveness of SS tumor cells and T-re(gs), to targeting with TNFR2 antagonistic antibodies. These results show TNFR2 antibodies are potent and efficacious in vitro.