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J Clin Oncol. 2016 Jul 20;34(21):2443-51. doi: 10.1200/JCO.2015.64.9558. Epub 2016 Apr 11.

KIR3DL1 Allelic Polymorphism and HLA-B Epitopes Modulate Response to Anti-GD2 Monoclonal Antibody in Patients With Neuroblastoma.

Author information

1
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.
2
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.

Abstract

PURPOSE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

PMID:
27069083
PMCID:
PMC4962735
DOI:
10.1200/JCO.2015.64.9558
[Indexed for MEDLINE]
Free PMC Article

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