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

: Antigen-targeting immunotherapies hinge on the accurate identification of immunogenic epitopes that elicit robust T-cell responses. However, current computational approaches focus primarily on MHC binding affinity, leading to high false-positive rates and limiting the clinical utility of antigen selection methods. : We developed the neoIM (for "neoantigen immunogenicity") model, a first-in-class, high-precision immunogenicity prediction tool that overcomes these limitations by focusing exclusively on overall CD8 T-cell response rather than MHC binding. neoIM, a random forest classifier, was trained solely on MHC-presented non-self peptides (n = 61.829). Its performance was assessed against that of currently existing alternatives on several in vitro immunogenicity datasets. In addition, its clinical impact was investigated in two retrospective analyses of clinical trial data by assessing the effect of neoIM-based antigen selection on the positive immunogenicity rate of personal vaccine designs. Finally, the potential for neoIM as a biomarker was investigated by assessing the correlation between neoIM scores and overall survival in a melanoma patient cohort treated with checkpoint inhibitors (CPI). : neoIM was found to substantially outperform publicly available tools in regards to in vitro benchmarks based on ELISpot assays, with an increase in predictive power of at least 30%, reducing false positives and improving target selection efficiency. In addition, using neoIM scores during patient-specific antigen prioritization and selection was shown to yield up to 50% more clinically actionable antigens for individual patients in two recent clinical trials. Finally, we showed that neoIM could further refine response prediction to checkpoint inhibition therapy, further demonstrating the importance of evaluating neoantigen immunogenicity. : These findings establish neoIM as the first computational tool capable of accurately predicting epitope immunogenicity beyond MHC affinity. By enabling more precise target discovery and prioritization, neoIM has the potential to accelerate the development of next-generation antigen-based immunotherapies.