Rescue of impaired NK cell activity in hodgkin lymphoma with bispecific antibodies in vitro and in patients.

Abstract

Natural killer (NK) cells represent a key component of the innate immune system against cancer. Nevertheless, malignant diseases arise in immunocompetent individuals despite tumor immunosurveillance. Hodgkin lymphoma (HL) is characterized by CD30(+) tumor cells and a massive infiltration of immune effector cells in affected lymph nodes. The latter obviously fail to eliminate the malignant cell population. Here, we tested for functional NK cell defects in HL and suggest an improvement of NK function by therapeutic means. We demonstrate that peripheral NK cells (pNK) from patients with HL fail to eliminate HL cell lines in ex vivo killing assays. Impaired NK cell function correlated with elevated serum levels of soluble ligands for NK cell receptors NKp30 (BAG6/BAT3) and NKG2D (MICA), factors known to constrict NK cell function. In vitro, NK cell cytotoxicity could be restored by an NKG2D/NKp30-independent bispecific antibody construct (CD30xCD16A). It artificially links the tumor receptor CD30 with the cytotoxicity NK cell receptor CD16A. Moreover, we observed that NK cells from patients treated with this construct were generally activated and displayed a restored cytotoxicity against HL target cells. These data suggest that reversible suppression of NK cell activity contributes to immune evasion in HL and can be antagonized therapeutically.

• Authors: Katrin S Reiners, Jörg Kessler, Maike Sauer, Achim Rothe, Hinrich P Hansen, Uwe Reusch, Christian Hucke, Ulrike Köhl, Horst Dürkop, Andreas Engert, Elke Pogge von Strandmann
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 21 Issue 4 Pg. 895-903 (Apr 2013) ISSN: 1525-0024 [Electronic] United States
• PMID: 23459515 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Bispecific

Topics

• Antibodies, Bispecific (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cells, Cultured
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Hodgkin Disease (therapy)
• Humans
• Immunohistochemistry
• Killer Cells, Natural (immunology)