Predicting Neoantigen Immunogenicity from In Vivo Immune Editing

Sears, T. J.; Lee, K.-h.; Munoz Perez, M.; Rasmussen, R.; Pagadala, M. S.; Tanaka, K.; Subramanian, A.; Moding, E. J.; Zanetti, M.; Carter, H.

doi:10.64898/2026.09.17.752425

bioRxiv · 10.64898/2026.09.17.752425

Predicting Neoantigen Immunogenicity from In Vivo Immune Editing

Sears, T. J.·Lee, K.-h.·Munoz Perez, M.·Rasmussen, R.·Pagadala, M. S.·Tanaka, K.·Subramanian, A.·Moding, E. J.·Zanetti, M.·Carter, H.

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Abstract

Neoantigen immunogenicity prediction is fundamental to personalized cancer vaccines, tumor-infiltrating lymphocyte (TIL) therapy, and TCR-T cell engineering. Existing computational predictors rely primarily on in-vitro correlates of peptide presentation or models trained against assay-based reactivity, and they are typically validated within a single therapeutic setting. We reasoned that the most direct evidence of neoantigen immunogenicity is longitudinal in-vivo elimination: under immune checkpoint blockade (ICB), subclones bearing recognized neoantigens are selectively depleted over time. Here, we present the Neoantigen Elimination Model (NEMo), a two-compartment (CD8 and CD4) machine learning classifier trained on the in-vivo editing (IVE) of neoantigens across serially sequenced, ICB-treated tumors. By using mechanistically inspired NeoPrecis features designed to capture determinants of immunogenicity beyond MHC binding affinity, NEMo recovered assay-confirmed immunogenic neoantigens across four independent, unseen clinical settings -- pre-existing immunogenicity screening, personalized cancer vaccines, TIL therapy, and a radiotherapy +/- ICB ctDNA cohort -- and stratified progression-free survival more strongly than ELISPOT-confirmed reactivity. The editing signal further revealed an immune-evasion architecture in which oncogenic drivers and neoantigens restricted to lost or silenced HLA alleles are systematically spared from editing.

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Sears, T. J., Lee, K.-h., Munoz Perez, M., Rasmussen, R., Pagadala, M. S., Tanaka, K., Subramanian, A., Moding, E. J., Zanetti, M., Carter, H.. 2026-09-18. Predicting Neoantigen Immunogenicity from In Vivo Immune Editing. https://doi.org/10.64898/2026.09.17.752425

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