title: 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: Department I of Internal Medicine, Laboratory of Immunotherapy, University Clinic of Cologne, Cologne, Germany.
authors: Katrin S
authors: KS
authors: Reiners
authors: Jörg
authors: J
authors: Kessler
authors: Maike
authors: M
authors: Sauer
authors: Achim
authors: A
authors: Rothe
authors: Hinrich P
authors: HP
authors: Hansen
authors: Uwe
authors: U
authors: Reusch
authors: Christian
authors: C
authors: Hucke
authors: Ulrike
authors: U
authors: Köhl
authors: Horst
authors: H
authors: Dürkop
authors: Andreas
authors: A
authors: Engert
authors: Elke Pogge
authors: EP
authors: von Strandmann
mesh_terms: D018033:Antibodies, Bispecific / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006689:Hodgkin Disease / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific