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

Leukemia. 2019 May;33(5):1206-1218. doi: 10.1038/s41375-018-0292-9. Epub 2018 Oct 24.

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 (Tregs). Potent human-directed TNFR2 antagonistic antibodies have been created that preferentially target the TNFR2 oncogene and tumor-infiltrating TNFR2+ Tregs. 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 Treg/T effector (Teff) ratios and the responsiveness of tumor and infiltrating Tregs 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+ Tregs of SS subjects are also killed with TNFR2 antagonism. Beneficial and rapid expansion of Teff was observed. The combination of Treg inhibition and Teff expansion brought the high Treg/Teff ratio to normal. Our findings suggest a marked responsiveness of SS tumor cells and Tregs, to targeting with TNFR2 antagonistic antibodies. These results show TNFR2 antibodies are potent and efficacious in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology*
  • Biomarkers
  • Cell Line, Tumor
  • Cell Proliferation
  • Dipeptidyl Peptidase 4 / metabolism
  • Gene Expression*
  • Humans
  • Immunophenotyping
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Neoplasm Staging
  • Receptors, Tumor Necrosis Factor, Type II / antagonists & inhibitors*
  • Receptors, Tumor Necrosis Factor, Type II / genetics*
  • Sezary Syndrome / drug therapy
  • Sezary Syndrome / genetics*
  • Sezary Syndrome / pathology*
  • T-Lymphocytes, Regulatory / drug effects*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*

Substances

  • Antibodies, Monoclonal
  • Biomarkers
  • Receptors, Tumor Necrosis Factor, Type II
  • Dipeptidyl Peptidase 4