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

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<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.

A systematic review reveals conflicting evidence for the prevalence of antibodies against the sialic acid ‘xenoautoantigen’ Neu5Gc in humans and the need for a standardised approach to quantification

“…A complicated picture: the anti-Neu5Gc response in humans and the methods used to study it Inconsistent, often contradictory findings are reflected across the whole field of research into the implications of Neu5Gc in human health and disease. Many studies suggest that immune responses against Neu5Gc may be a putative driver of cancer (Diccianni et al, 2018;Bashir et al, 2020), autoimmune disease (Eleftheriou et al, 2014a), inflammation (Pham et al, 2009), and degenerative conditions (Martin et al, 2021), with some even speculating that CMAH loss and resulting changes to the sialic acid landscape may have contributed to the increase in brain size and plasticity that allowed the development of human intelligence (Davies and Vark, 2013). Equally, many studies report no discernible link between disease and the presence of anti-Neu5Gc antibodies (Eleftheriou et al, 2014b;Le Berre et al, 2017;Soulillou et al, 2018), and some even propose that anti-Neu5Gc antibodies may have a protective role, particularly against allergic disease (Frei et al, 2018;Frei et al, 2019).…”

Blood Type Diets (BTD) and Aging: An Overview

“…CCDs have been observed between environmental and food allergens through high levels of IgE AGA [161]. For example, there are circulating AGA in healthy humans against N-glycolylneuraminic acid (Neu5Gc) and galactose alpha-1,3-galactose (α-gal), glycans present in dairy products and red meats [162].…”