Abstract LB-048: Impact of KIR/KIR ligand genotype for neuroblastoma patients in a Phase 3 COG immunotherapy trial
Authors: Erbe Amy K. , Wang Wei , Carmichael Lakeesha , Kim KyungMann , Reville Patrick K. , London Wendy B. , Hank Jacquelyn A. , Diccianni Mitchell B. , Naranjo Arlene , Hogarty Michael , Park Julie R. , Yu Alice L. , Sondel Paul M. 
Published: July 2017

Abstract
Introduction: High-risk neuroblastoma (NBL) patients (pts) enrolled in a COG Phase 3 clinical trial (ANBL0032) were randomized to isotretinoin (RA) alone or Immunotherapy: dinutuximab (anti-GD2 mAb) + IL2 + GMCSF + RA (Yu et al., NEJM, 2010). Dinutuximab acts via antibody-dependent cell-mediated cytotoxicity by innate immune cells, including NK cells. NK cells express Killer Immunoglobulin-like Receptors (KIRs); most of the inhibitory KIRs have KIR-ligands that belong to the HLA class I family. Specifically, KIR2DL1 is a receptor for HLA-C2, KIR2DL2 and KIR2DL3 are receptors for HLA-C1, and KIR3DL1 is a receptor for HLA-Bw4. Some prior studies of anti-GD2 mAb immunotherapies have shown associations with outcome based on the genotypes of these inhibitory KIR/KIR ligand relationships. We investigated whether certain KIR/KIR-ligand genotypes were associated with event-free survival (EFS) and overall survival (OS) in this trial.
Methods: Of the 226 pts randomized, 174 pts had DNA allowing evaluation of genotype correlations with outcome (RA: n=86; Immunotherapy: n=88; &gt;5yr follow-up if no event). We looked for associations of inhibitory KIRs with their respective KIR-ligands and clinical outcome. Log-rank tests and Cox proportional hazards regression models were used to compare EFS/OS by genotype group; adjustment was made for non-proportional hazards as needed using time-dependent covariates.
Results: We found that certain, hypothesis-identified, inhibitory KIR/KIR-ligand combinations were associated with improved clinical outcome. Namely, pts that were both KIR2DL2+/HLA-C1+ and KIR3DL1+/HLA-Bw4+ had improved EFS and OS if treated with Immunotherapy (n=23) vs. RA (n=26) (5-yr EFS: 61% vs. 27%, p=0.02; 5-yr OS: 91% vs. 34%, p=0.007). Conversely, for pts that were not both KIR2DL2+/HLA-C1+ and KIR3DL1+/HLA-Bw4+, we found insufficient evidence to support an improvement in EFS or OS with Immunotherapy (n=65) vs. RA (n=60) (5-yr EFS: 57% vs. 53%, p=0.76; 5-yr OS: 68% vs. 68%, p=0.66).
Conclusions: Our data suggest that KIR/KIR-ligand genotype may be predictive of benefit from Immunotherapy. The impact of immunotherapy appears different for pts that were both KIR2DL2+/HLA-C1+ and KIR3DL1+/HLA-Bw4+ vs. those that were not both KIR2DL2+/HLA-C1+ and KIR3DL1+/HLA-Bw4+. Validation of these KIR/KIR-ligand associations in similarly treated high-risk NBL patients would be required prior to proposing their prospective use in the aid of clinical treatment decisions. Further investigation of KIR/KIR-ligand genotypes may also clarify their role and the role of NK cells in the activity of this form of cancer immunotherapy.
Citation Format: Amy K. Erbe, Wei Wang, Lakeesha Carmichael, KyungMann Kim, Patrick K. Reville, Wendy B. London, Jacquelyn A. Hank, Mitchell B. Diccianni, Arlene Naranjo, Michael Hogarty, Julie R. Park, Alice L. Yu, Paul M. Sondel. Impact of KIR/KIR ligand genotype for neuroblastoma patients in a Phase 3 COG immunotherapy trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-048. doi:10.1158/1538-7445.AM2017-LB-048