# What makes a neoantigen actually immunogenic?

Source: https://onco.cc/ideas/idea-neoantigen-immunogenicity-rules/  
OnCo record `idea-neoantigen-immunogenicity-rules` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Vaccines can now encode dozens of a tumour's mutations, but only a minority provoke useful T cells. Learning the rules would make vaccines smaller, cheaper, and stronger.

## Summary

This open question asks what makes a neoantigen immunogenic: vaccines encode dozens of mutations but only a minority provoke useful T cells, and learning the rules would make vaccines smaller and stronger. Prediction relies on HLA binding and expression, but immunogenicity also depends on TCR repertoire, dissimilarity to self, clonality and dendritic cell presentation (Antigen presentation & immune editing pathway). Long-term responders in the Balachandran pancreatic cohort provide ground truth, and INTerpath-001 follow-up supplies immune-monitoring data. The hypothesis is that a model trained on T-cell responses from trials of Intismeran autogene and other Personalised neoantigen (mRNA) vaccines can cut epitopes per vaccine from 34 to under 10.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- Tags: mechanism; open-question
- Hypothesis: Immunogenic neoantigens can be predicted with >50% precision by models trained on validated T-cell responses from vaccine trials, cutting the number of epitopes needed per vaccine from 34 to under 10.
- Rationale: INTerpath-001 success and autogene cevumeran follow-up supply immune-monitoring data; TCR-sequencing and antigen-specific assays are scalable.
- Proposed test: Pooled analysis of vaccine-trial immunomonitoring to train and prospectively validate an immunogenicity model; then a randomised trial of model-selected 10-epitope vs standard 34-epitope vaccines with T-cell response as primary endpoint.
- Maturity: preclinical-evidence

## Sources

- Wells et al., Key parameters of tumour epitope immunogenicity revealed through a consortium approach (Cell 2020): https://doi.org/10.1016/j.cell.2020.09.015

## Connected records

- technologies: [Personalised neoantigen (mRNA) vaccines](https://onco.cc/technologies/neoantigen-mrna-vaccine/), [TCR-T cell therapy](https://onco.cc/technologies/tcr-t/)
- drugs: [Autogene cevumeran](https://onco.cc/drugs/autogene-cevumeran/), [Intismeran autogene](https://onco.cc/drugs/intismeran-autogene/)
- institutions: [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/), [National Cancer Institute (NIH)](https://onco.cc/institutions/nci/), [Siteman Cancer Center, Washington University](https://onco.cc/institutions/wustl-siteman/)
- pathways: [Antigen presentation & immune editing](https://onco.cc/pathways/antigen-presentation-immunoediting/)
- terms: [Neoantigen](https://onco.cc/terms/neoantigen/)
- key papers: [Key Parameters of Tumor Epitope Immunogenicity Revealed Through a Consortium Approach Improve Neoantigen Prediction](https://onco.cc/key-papers/paper-wells-cell/)

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