Abstract LB-300: Natural antibodies to non-human glycans Neu5Gc and alpha-gal correlate with outcome of high-risk neuroblastoma patients treated with dinutuximab on COG ANBL0032 and ANBL0931
Authors: Diccianni Mitchell B. , Mielke Jenna , Williams Richard , Messer Karen , Ozkaynak Fevzi , Gilman Andrew L. , Naranjo Arlene , London Wendy , Sondel Paul M. , Park Julie , Yu Alice L. ,   Childrens Oncology Group
Published: August 2018

Abstract
Immunotherapy with ch14.18 (dinutuximab) has significantly improved the survival of high-risk neuroblastoma patients, though late relapses and allergic reaction remain concerning. N-glycolylneuraminic acid (Neu5Gc) and galactose alpha-1,3-galactose (α-gal) are glycans present in most mammals except human. Humans have circulating antibodies against these glycans due to their presence in dairy products and red meats. We investigated whether anti-glycan antibodies influence efficacy or allergic reactions associated with dinutuximab. Using ELISA, we measured anti-Neu5Gc and anti-α-gal IgG and IgE levels in plasma collected from courses 1 (days -1 & 6), 4 (days 80 & 90) & 5 (days 111 & 118) of patients on two immunotherapy trials of neuroblastoma (ANBL0032 n= 219; ANBL0931 n=100). Levels of IgG and IgE antibodies against both glycans were highest at pretreatment, decreasing significantly over the entire course of therapy as well as within each course of therapy (p&lt;0.001, Wilcoxon signed rank). For patients on ANBL0032 immunotherapy, anti-α-gal was 924 ± 208 ng/ml (n=118) at pretreatment, decreasing to 102 ± 573 ng/ml (n=82) at day 118. Similar decreases in anti-glycan levels were also noted in patients treated with isotretinoin alone. No association between anti-glycan levels and the occurrence of anaphylaxis, urticaria or other allergic reaction during immunotherapy was observed. Patients were next dichotomized by median value into low vs. high anti-glycan subgroups and associations with EFS and OS assessed using log-rank test. While there was no correlation of anti-glycan levels at pretreatment with outcome, patients treated with immunotherapy on ANBL0032 with lower levels of anti-α-gal and anti-Neu5Gc IgG at later assessment times were significantly associated with better EFS. For example, patients with less than median levels of anti-α-gal on day 90 (n=93, p=0.05) and day 118 (n=86, p=0.05), and anti-Neu5Gc on day 90 (p=0.009) and day 118 (p=0.05), had better EFS. These results remained valid when the ANBL0032 and ANBL0931 cohorts were combined. In contrast, there was no significant correlation of anti-glycan levels and OS with immunotherapy, or EFS or OS in the non-immunotherapy cohort at any treatment timepoint. Our results suggest that lower levels of circulating antibodies against non-human glycans in neuroblastoma patients treated with dinutuximab are associated with better EFS, presumably due to less interaction of glycans on dinutuximab.
Citation Format: Mitchell B. Diccianni, Jenna Mielke, Richard Williams, Karen Messer, Fevzi Ozkaynak, Andrew L. Gilman, Arlene Naranjo, Wendy London, Paul M. Sondel, Julie Park, Alice L. Yu, Childrens Oncology Group. Natural antibodies to non-human glycans Neu5Gc and alpha-gal correlate with outcome of high-risk neuroblastoma patients treated with dinutuximab on COG ANBL0032 and ANBL0931 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-300.