title: Neuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR 2DS2 treated by long-term infusion of anti-GD2antibody ch14.18/CHO show higher ADCC levels and improved event-free survival.
abstract: Polymorphisms in Fc-gamma-receptor (FCGR) genes as well as killer cell immunoglobulin-like receptor (KIR) and KIR ligand (KIRL) repertoires may influence antitumor effects of monoclonal antibodies (mAb). Here, we systematically analyzed high- and low-affinity FCGR2A and -3A genotypes as well as stimulating and inhibitory KIR/KIRL combinations in 53 neuroblastoma (NB) patients treated by long-term infusion (LTI) of anti-GD2IgG1 Ab ch14.18/CHO using validated real-time PCR methods. Patients with high-affinity FCGR2A and -3A genotypes showed a higher level of Ab-dependent cell-mediated cytotoxicity (ADCC) on day 8 after the start of ch14.18/CHO and superior event-free survival (EFS) compared to patients with low FCGR genotypes. Similar observations were made for patients with stimulatory KIR/KIRL haplotype B (combination of KIR genes including activating receptor genes) compared to inhibitory haplotype A (a fixed set of genes encoding for inhibitory receptors, except 2DS4) and stronger effects were found in patients when haplotype B and high-affinity FCGRs were combined. Surprisingly, independent analysis of KIRs showed a major role of activating KIR 2DS2 for high ADCC levels and prolongation of EFS. The greatest effect was observed in 2DS2-positive patients that also had high-affinity FCGR2A and -3A genotypes. In summary, the presence of the activating KIR 2DS2 has a major effect on ADCC levels and survival in NB patients treated by LTI of ch14.18/CHO and may therefore be a useful biomarker in combination with FCGR polymorphisms for Ab-based immunotherapies.
authors.affiliation: Department of Pediatric Oncology and Hematology, University Medicine Greifswald , Greifswald, Germany.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Siebert
authors.affiliation: Department of Pediatric Oncology and Hematology, University Medicine Greifswald , Greifswald, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Jensen
authors.affiliation: Department of Pediatric Oncology and Hematology, University Medicine Greifswald , Greifswald, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Troschke-Meurer
authors.affiliation: Department of Pediatric Oncology and Hematology, University Medicine Greifswald , Greifswald, Germany.
authors.forename: Maxi
authors.initials: M
authors.lastname: Zumpe
authors.affiliation: Department of Pediatric Oncology and Hematology, University Medicine Greifswald , Greifswald, Germany.
authors.forename: Madlen
authors.initials: M
authors.lastname: Jüttner
authors.affiliation: Department of Pediatric Oncology and Hematology, University Medicine Greifswald , Greifswald, Germany.
authors.forename: Karoline
authors.initials: K
authors.lastname: Ehlert
authors.affiliation: Department of Pediatric Oncology and Hematology, University Medicine Greifswald , Greifswald, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Kietz
authors.affiliation: Department of Pediatric Oncology and Hematology, University Medicine Greifswald , Greifswald, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Müller
authors.affiliation: Department of Pediatric Oncology and Hematology, University Medicine Greifswald , Greifswald, Germany.
authors.forename: Holger N
authors.initials: HN
authors.lastname: Lode
keywords: Antibody-dependent cell-mediated cytotoxicity (ADCC); Fc-gamma-receptor polymorphisms (FCGR); KIR ligand (KIRL); ch14.18/CHO; killer-cell immunoglobulin-like receptor (KIR); neuroblastoma