title: KIR3DL1 Allelic Polymorphism and HLA-B Epitopes Modulate Response to Anti-GD2 Monoclonal Antibody in Patients With Neuroblastoma.
abstract: In patients with neuroblastoma (NB), treatment with anti-GD2 monoclonal antibody (mAb) directs natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against tumor cells. However, tumor cytotoxicity is attenuated by ligation of inhibitory killer immunoglobulin-like receptors (KIRs) by HLA class I molecules. KIR3DL1 polymorphism influences its ability to engage HLA-Bw4 ligands. We tested the hypothesis that poorly interacting combinations of KIR3DL1 and HLA ligands are more permissive of mAb-mediated antitumor effect.
  
  
  
  KIR3DL1 and HLA-B subtyping were performed with a multiplex intermediate-resolution polymerase chain reaction assay for a cohort of 245 patients who were treated with antibody 3F8 for high-risk NB. Patient outcomes were analyzed according to expected degree of interaction between KIR3DL1 and HLA-B subtypes and grouped as strong, weak, or noninteractors. A comparison of NK response to 3F8 mAb opsonized NB cells between strong- and noninteracting donors was performed by flow cytometry.
  
  
  
  KIR3DL1 and HLA-B subtype combinations associated with noninteraction as a result of lack of receptor expression [KIR3DL1(-)], failure of interaction with inhibitory ligands [KIR3DS1(+)], or absence of KIR ligands resulted in significantly improved overall and progression-free survival. Patients with KIR3DL1 and HLA-B subtype combinations that were predictive of weak interaction had superior outcomes compared with those that were predictive of strong interaction; however, both groups were inferior to those with noninteracting subtype combinations. In vitro analysis of 3F8-mediated ADCC showed that KIR3DL1(-) and 3DS1(+) NK cells were insensitive to inhibition by HLA-Bw4-expressing NB targets.
  
  
  
  We conclude that KIR3LD1 and HLA-B allele combinations can have a prognostic impact on patient survival after treatment with anti-GD2 mAb that relies on NK-ADCC. The survival advantage seen in noninteracting combinations supports the therapeutic disinhibition of individuals with strongly interacting KIR and ligand pairs.
authors.affiliation: Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Forlenza
authors.affiliation: Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY.
authors.forename: Jeanette E
authors.initials: JE
authors.lastname: Boudreau
authors.affiliation: Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY.
authors.forename: Junting
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY.
authors.forename: Jean-Benoît
authors.initials: JB
authors.lastname: Le Luduec
authors.affiliation: Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chamberlain
authors.affiliation: Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY.
authors.forename: Glenn
authors.initials: G
authors.lastname: Heller
authors.affiliation: Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY.
authors.forename: Nai-Kong V
authors.initials: NK
authors.lastname: Cheung
authors.affiliation: Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Jean-Benoît Le Luduec, Elizabeth Chamberlain, Glenn Heller, Nai-Kong V. Cheung, and Katharine C. Hsu, Memorial Sloan Kettering Cancer Center; and Katharine C. Hsu, Weill Cornell Medical College, New York, NY. hsuk@mskcc.org.
authors.forename: Katharine C
authors.initials: KC
authors.lastname: Hsu
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D000939:Epitopes; D005732:Gangliosides / Q000276:immunology*; D015235:HLA-B Antigens / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000401:mortality; D011110:Polymorphism, Genetic; D054341:Receptors, KIR3DL1 / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D005732:Gangliosides; D015235:HLA-B Antigens; C515083:KIR3DL1 protein, human; D054341:Receptors, KIR3DL1; C019403:ganglioside, GD2