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...

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Bibliographic Details
Published in:Leukemia 2019-05, Vol.33 (5), p.1206
Main Authors: Torrey, H, Khodadoust, M, Tran, L, Baum, D, Defusco, A, Kim, Y H, Faustman, D L
Format: Article
Language:English
Subjects:
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
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Summary: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 ). Potent human-directed TNFR2 antagonistic antibodies have been created that preferentially target the TNFR2 oncogene and tumor-infiltrating TNFR2 T . 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 /T effector (T ) ratios and the responsiveness of tumor and infiltrating T 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 of SS subjects are also killed with TNFR2 antagonism. Beneficial and rapid expansion of T was observed. The combination of T inhibition and T expansion brought the high T /T ratio to normal. Our findings suggest a marked responsiveness of SS tumor cells and T , to targeting with TNFR2 antagonistic antibodies. These results show TNFR2 antibodies are potent and efficacious in vitro.
ISSN:1476-5551
DOI:10.1038/s41375-018-0292-9