Targeted killing of TNFR2-expressing tumor cells and T(regs) by TNFR2 antagonistic antibodies in advanced Sézary syndrome

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.