HLA Class II Alleles DRB1*11:01 and DQB1*03:01 Unmask Immunogenetic Susceptibility to Anti-Nivolumab Antibodies in Combination with Ipilimumab.

Abstract

Biologic combinations that modulate immune responses are increasingly used in oncology, enhancing anti-tumor immunity but also raising the risk of anti-drug antibody (ADA) development. Nivolumab administered in combination with ipilimumab results in significantly higher nivolumab ADA incidence (44%) compared to nivolumab monotherapy (12%). While previous analyses showed no clinical impact of nivolumab ADA on safety and efficacy for the combination, it provided a unique dataset to evaluate genetic predispositions to nivolumab ADA development and impact of co-administered ipilimumab. HLA Class II alleles were evaluated for associations with nivolumab ADA. Logistic regression analyses were performed on HLA-DRB1, DQB1, and DQA1 alleles from melanoma subjects treated with nivolumab plus ipilimumab and nivolumab alone. Univariate screening identified candidate alleles that were associated with immunogenicity. This was followed by multivariable modeling to assess independent and combined effects after accounting for sex, age and region. Multivariable analyses indicated that DRB1*11:01 (Odds Ratio (OR) = 2.5, p-value (p) = 0.011) and DQB1*03:01 (OR = 3.2, p = 0.0002) were each significantly associated with nivolumab ADA positivity in combination therapy. The combined presence of both alleles conferred an even stronger association (OR = 4.1, p = 0.0017). No significant associations were observed for nivolumab monotherapy. In silico predictions and MHC-associated peptide proteomics (MAPPs) confirmed high-affinity binding of a nivolumab framework peptide (a known Treg epitope) to DRB1*11:01. DRB1*11:01 and DQB1*03:01 may predict anti-nivolumab antibody development in the context of combination therapy. These findings underscore the role of host genetics and immune modulation by ipilimumab in shaping immunogenicity.