Abstract 2459: KIR3DL1 and HLA-B subtype combinations predict the efficacy of 3F8 monoclonal antibody therapy for neuroblastoma
Authors: Forlenza Christopher J. , Boudreau Jeanette E. , Zheng Junting , Heller Glenn , Cheung Nai-Kong V. , Hsu Katharine C. 
Published: August 2015

Abstract
Background: Treatment of high-risk neuroblastoma (NB) with anti-GD2 monoclonal antibody (3F8) recruits Natural Killer (NK) cells for antibody-dependent-cell mediated cytotoxicity (ADCC). NK reactivity is triggered when the signals for activation outweigh inhibition; principal among the inhibitory ligands for NK cells are HLA, detected by inhibitory killer Ig-like receptors (KIR).
Among receptor-ligand partnerships, KIR3DL1 and HLA-B exhibit the greatest diversity. Variation in KIR3DL1 surface expression (null, low or high) and dimorphism at HLA-Bw4 amino-acid sequence 80 (isoleucine v. threonine) are associated with varied strengths of interaction. We hypothesized that KIR3DL1/HLA-Bw4 partnerships could influence the outcome of 3F8 treatment by varying the strength of inhibitory signaling.
Methods: KIR3DL1 and HLA-B subtype combinations were assessed in a cohort of 245 patients with high-risk NB treated with 3F8 by medium-resolution PCR. Patients were grouped based on strength of interaction expected from KIR3DL1 subtype/HLA-Bw4: Strong-interactors (3DL1-high+Bw4-80I; 3DL1-low+Bw4-80T); weak-interactors (3DL1-high+Bw4-80T; 3DL1-low+Bw4-80I); and the non-interactors, where no KIR3DL1/Bw4 interaction is expected (3DL1-null or KIR3DS1 + any HLA-Bw4; Bw6/Bw6 + any 3DL1) were compared for their influences on overall and progression-free survival.
Results: The frequency of KIR3DL1/HLA-B partnerships were: strong-interactors 25.3%, weak-interactors 22.4%, and non-interactors 52.2%. The 5-year progression-free survival (PFS) for strong-interactors, weak-interactors, and non-interactors was 28.6% [95% CI:19.3-42.2%], 34.1% [95% CI:23.5-49.4%] and 52.2% [95% CI:44.1-61.7%], respectively (p = 0.005). The 5-year overall survival (OS) for strong-interactors, weak-interactors, and non-interactors was 49.2% [95% CI: 38.3-63.2%], 44.8% [95% CI:33.3-60.3%] and 63.1% [95% CI:55.2-72.2%] (p = 0.013). When controlling for age, lactate dehydrogenase, and disease status at time of treatment the benefit of non-interacting subtypes was maintained for PFS (HR 0.41, [95% CI: 0.27-0.62], p = &lt;0.001) and OS (HR 0.42, [95% CI:0.26-0.67], p = &lt;0.001).
Conclusions: In patients with NB treated with 3F8, non-interacting subtypes are predictive of improved progression-free and overall survival. Comparatively, patients whose KIR3DL1 and HLA-B allele subtypes predict for strong and weak interaction exhibit high and intermediate risk for disease progression. Collectively, our findings support KIR3DL1 and HLA-B subtype analysis for prognostication and indicate disinhibition of NK cells as a therapeutic target.
Citation Format: Christopher J. Forlenza, Jeanette E. Boudreau, Junting Zheng, Glenn Heller, Nai-Kong V. Cheung, Katharine C. Hsu. KIR3DL1 and HLA-B subtype combinations predict the efficacy of 3F8 monoclonal antibody therapy for neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2459. doi:10.1158/1538-7445.AM2015-2459