From Universal Aspiration to Precision Immunization: A Hypothesis Framework for Antigen-Defined, HLA-Restricted Cancer Vaccines.

Cancer vaccination addresses four distinct problems: preventing oncogenic infection, intercepting premalignant clones, clearing molecular residual disease, and treating established cancer. This hypothesis framework proposes seven sequential gates for antigen-defined, HLA-restricted T-cell vaccines: tumor specificity, natural peptide-HLA presentation, population coverage, persistence under immune selection, selective T-cell recognition, manufacturability, and randomized clinical benefit. The proposed architecture combines a pre-manufactured core of validated shared antigens with a personalized shell when shared targets do not cover the tumor or the patient's HLA type. Current evidence supports restraint. Individualized mRNA neoantigen therapy with pembrolizumab produced a recurrence-free-survival signal in a randomized phase 2b melanoma trial, whereas a 20-antigen shared cassette produced immunodominant responses toward encoded TP53 epitopes rather than the KRAS neoantigens carried by the tumors. No quantitative coverage or persistence score is presented because the required population frequencies and persistence measurements cannot be supplied reliably from the published record. Four falsifiable predictions define the experiments needed to test presentation-first selection, antigen persistence, escape-route independence, and biomarker-directed treatment. The framework is therefore a research agenda, not a validated decision tool.