Accelerating Neoantigen Discovery: A High-Throughput Approach to Immunogenic Target Identification.

Area of Science:

• Computational immunology
• Cancer immunotherapy
• Bioinformatics

Background:

• Antigen-targeting immunotherapies rely on identifying immunogenic epitopes for T-cell responses.
• Current methods focusing on MHC binding affinity yield high false positives, limiting clinical utility.
• Accurate prediction of neoantigen immunogenicity is crucial for effective cancer vaccine and therapy design.

Purpose of the Study:

• To develop a novel computational tool, neoIM, for high-precision prediction of neoantigen immunogenicity.
• To evaluate neoIM's performance against existing tools using in vitro and clinical trial data.
• To assess neoIM's potential as a biomarker for predicting response to checkpoint inhibitor therapy.

Main Methods:

• Developed neoIM, a random forest classifier trained on MHC-presented non-self peptides (n=61,829).
• Assessed neoIM performance against existing tools on in vitro immunogenicity datasets (ELISpot assays).
• Conducted retrospective analyses of clinical trial data to evaluate neoIM-based antigen selection and its correlation with overall survival in melanoma patients treated with checkpoint inhibitors (CPI).

Main Results:

• neoIM significantly outperformed existing tools on in vitro benchmarks, increasing predictive power by at least 30% and reducing false positives.
• NeoIM-based antigen selection identified up to 50% more clinically actionable antigens per patient in two clinical trials.
• NeoIM scores showed a correlation with overall survival in melanoma patients treated with CPI, indicating its potential as a predictive biomarker.

Conclusions:

• NeoIM is the first computational tool to accurately predict epitope immunogenicity beyond MHC binding affinity.
• NeoIM enables more precise neoantigen discovery and prioritization, potentially accelerating the development of next-generation immunotherapies.
• The tool's ability to refine response prediction to checkpoint inhibition therapy highlights the importance of evaluating neoantigen immunogenicity.