Hyperprogression under Immune Checkpoint Inhibitor: a potential role for germinal immunogenetics

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Hyperprogressive disease (HPD) is an adverse response to immune checkpoint inhibitors (ICIs) like anti-PD-1/anti-PD-L1 agents.
• The host's genetic factors may influence the development of HPD.

Purpose of the Study:

• To investigate whether single nucleotide polymorphisms (SNPs) in immune-related genes are associated with HPD in cancer patients treated with ICIs.
• To identify potential genetic biomarkers for predicting HPD.

Main Methods:

• DNA from 98 cancer patients receiving ICI monotherapy was analyzed for SNPs in PD-1, PD-L1, IDO1, and VEGFR2 genes.
• Tumor growth kinetics were assessed using the TGK_R (tumor growth ratio), with HPD defined as TGK_R≥2.
• Univariate and multivariate analyses were performed to identify associations between HPD and genetic variations, age, and toxicity.

Main Results:

• HPD was observed in 14% of patients and was linked to shorter overall survival.
• Significant associations were found between HPD and older age (≥70 years), immune-related toxicity, and specific SNPs in VEGFR2 (rs1870377) and PD-L1 (rs2282055).
• Multivariate analysis confirmed age, VEGFR2 rs1870377, and PD-L1 rs2282055 as independent predictors of HPD.

Conclusions:

• Specific SNPs in VEGFR2 and PD-L1, along with older age, are associated with an increased risk of HPD.
• Immunogenetic profiling may offer valuable predictive biomarkers for ICI therapy.
• Further research is warranted to integrate immunogenetics into clinical decision-making for cancer immunotherapy.