Beyond priming: a sequential, feedback-guided adjuvant framework for therapeutic cancer peptide vaccines in immunologically cold tumors.

Therapeutic cancer vaccines can generate measurable antigen-specific immune responses in humans, yet tumor regression is often incomplete, inconsistent, or short-lived. In immunologically cold tumors, this pattern may reflect not an absolute inability to prime immunity, but difficulty advancing induced immunity through the full sequence required for tumor control. Peripheral blood responses may be real and still be biologically inadequate if they contract early, fail to acquire productive trafficking programs sufficient for tissue entry, lose functional competence under chronic antigen stress, or remain constrained by the suppressive tumor microenvironment. The manuscript advances a sequential, feedback-guided adjuvant framework in which peptide vaccination remains the backbone but is preceded and followed by distinct support phases. A Phase 0 immune-readiness step, potentially using IL-7 (e.g., CYT107), is intended to improve the baseline substrate before antigen exposure. Phase 1 priming uses peptide vaccination on a commonly used adjuvant backbone such as Montanide ISA-51 or poly-ICLC (Hiltonol), while radiation and/or STING-based strategies are treated as context-dependent enhancers rather than replacements for priming. IL-15-centered consolidation is then used to support expansion and persistence. A formal trafficking assessment follows so that blood-only success is not overinterpreted. IL-21 is positioned later as a persistence- and quality-support cytokine when response quality declines. The framework also addresses why otherwise rational protocols can fail at the chemokine-trafficking step: CXCR3-dependent tumor entry is not interchangeable with generic inflammation, CCR5 biology is context dependent, and IL-12, although biologically attractive and previously tested as a vaccine adjuvant, is best viewed here as an optional, context-specific amplifier rather than a universal backbone. Although organized as sequential phases, the framework is intended as a bottleneck-guided and iterative design logic in which phases may overlap, repeat, or be entered in partial parallel depending on the dominant biologic constraint. The central hypothesis is that vaccine programs that progress beyond priming into trafficking-competent and functionally sustained states are predicted to correlate more closely with disease control than programs judged mainly by early blood immunogenicity.