Immunopeptidomics-guided approach boosts neoantigen identification success to 83% in NSCLC patients

Despite advances with checkpoint inhibitor therapies, Non-Small Cell Lung Cancer (NSCLC) continues to have poor survival rates. Personalised cancer vaccines, leveraging short peptide neoantigens derived from tumor mutations, represent a promising precision medicine strategy. However, a significant challenge lies in accurately identifying therapeutically relevant neoantigens, as current prediction methods often yield low positive response rates, typically around 6%. This gap highlights the critical need for improved strategies to select functional neoantigens that can effectively stimulate a targeted anti-tumor immune response.

Researchers developed an immunopeptidomics approach to enhance neoantigen identification in 24 NSCLC patients (15 adenocarcinoma, 9 squamous cell carcinoma). They directly identified one neoantigen and, using whole exome sequencing, transcriptomics, and mass spectrometry-based immunopeptidomics, filtered predicted neoantigens. This filtering was based on observed cohort HLA peptide presentation patterns. The primary endpoint was the rate of positive functional immune responses elicited by the identified neoantigens, comparing their novel method against existing prediction strategies.

The novel immunopeptidomics-guided approach significantly improved the success rate of identifying functional neoantigens. The method achieved positive functional responses in 5 of 6 patients tested, demonstrating an impressive 83% success rate. This is a substantial improvement over the 6% success rate typically observed with existing methods. Furthermore, 13% of the putative neoantigens identified (9 out of 70) elicited strong immune responses. Bayesian modeling of their initial rules-based neoantigen selection further revealed patient-specific HLA peptide presentation patterns and propensities, underscoring the personalized nature of immune recognition. This data highlights the critical role of incorporating donor-specific HLA peptide presentation information.

The immunopeptidomics approach achieved positive functional responses in 5 of 6 patients tested (83% success rate), with 13% of putative neoantigens (9 out of 70) eliciting strong responses.