Abstract 5586: NK cell killer Ig-like receptor (KIR) genotype as a novel biomarker for neuroblastoma patients receiving Anti-GD2 monoclonal antibody 3F8

Abstract

Abstract Background: Natural killer (NK) cells are regulated by inhibitory killer Ig-like receptors (KIRs) that recognize specific HLA class I ligands. KIR-HLA genotypes are tightly linked to NK cell function and clinical outcomes in allogeneic and autologous hematopoietic stem cell transplantation (HSCT). Because NK cells contribute to antibody-dependent cellular cytotoxicity, we hypothesized that specific KIR-HLA genotypes may predict NK cell responsiveness to mAb therapy, and thus, may be useful clinically to identify patients likely to respond to mAb therapy. Methods: 76 children with high risk neuroblastoma received cyclophosphamide-containing induction chemotherapy followed by murine IgG3 monoclonal antibody 3F8 against ganglioside GD2 between 1993 and 2007. HLA and KIR genotyping was performed, and patients were segregated into KIR-HLA groups based on known functional KIR-HLA ligand relationships: KIR2DL2/2DL3 with HLA-CAsn80(HLA-C1 group), KIR2DL1 with HLA-C Lys80(HLA-C2 group), and KIR3DL1 with HLA-Bw4. Overall survival and progression-free survival were estimated by Kaplan-Meier method and hazard ratios by Cox regression. No adjustments were made for multiple comparisons. Comparisons of each end point were based on the log-rank statistics. Results: 63% of the 76 children lacked at least 1 HLA ligand for his/her inhibitory KIR. At 3 years, 80% of patients lacking any KIR ligand (n=46) were alive compared with 69% of patients with all HLA ligands present (n=30) (HR 0.41; 95% CI 0.17-0.98; P=0.04). 23/23 (100%) patients specifically lacking the HLA-Bw4 ligand for KIR3DL1 were alive at 3 years compared with 34/52 (67%) patients exhibiting HLA-Bw4 for KIR 3DL1 (n=52) (HR 0.20; 95% CI 0.05-0.87; P=0.02). Conclusion: KIR-HLA immunogenetics may be a novel biomarker for neuroblastoma patients receiving chemo-immunotherapy. The milieu of HSCT may not be required for NK cells to behave according to “missing ligand,” and KIR-HLA combinations may be predictive of outcome for other malignancies similarly treated with mAb. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5586.