Combinatorial-complete immunotherapy protocols: three proposed trial designs testing the seven-mode framework in immunotherapy-refractory cancers

The seven-mode framework for cancer immunotherapy (Monteiro 2026, Paper 3 in this series) predicts that combinatorial protocols engaging all seven failure modes of immune-mediated tumor control simultaneously will produce qualitatively different clinical outcomes from contemporary single-mode or narrow combination interventions. The framework's structural arguments are established. Its translational test requires specific trial designs in tumor populations where multiple failure modes are operative and where component interventions exist but have not been combined. This paper proposes three such trials: 1. A combinatorial-complete protocol in BRCA1/2-mutant triple-negative breast cancer building on the KEYNOTE-522 standard, with immune-first sequencing (intratumoral poly-ICLC plus mRNA neoantigen vaccine plus anti-PD-1 established before and during immunogenic chemotherapy, with anthracycline phase protected by IL-15 superagonist support or conditionally de-escalated for strong responders); 2. An extended autogene cevumeran protocol in resectable pancreatic ductal adenocarcinoma adding Mode 3 (stromal modification via anti-VEGF or FAK inhibition), Mode 5 (CD73/A2A inhibition), and Mode 6 (IL-15 superagonist) engagement to the established vaccine-checkpoint backbone; 3. A multi-mode protocol in microsatellite-stable metastatic colorectal cancer building on the FOLFOX-bevacizumab standard, adding intratumoral poly-ICLC, anti-PD-1, and IL-15 superagonist — the largest single immunotherapy-refractory population in oncology. For each trial the paper specifies population, intervention components mapped to the seven modes, comparator arm, endpoints, statistical design, biomarker strategy, anticipated toxicity, and feasibility. A central design principle — the chemotherapy-sequencing and dosing principle — governs all three: immunogenic-dose chemotherapy as immune trigger, immune priming established before or concurrent with cytoreduction, and myelosuppressive phases timed to avoid destroying primed T cells. The trials are framed as a modern Coley lineage: precise molecular descendants of Coley's intratumoral, sustained, innate-immune-activating approach, completed by the addition of checkpoint blockade (Mode 4) that Coley's era lacked. Each protocol uses FDA-approved or late-stage investigational components combined in ways that have not been systematically tested. The framework predicts these combinations will convert immunotherapy-refractory populations into immunotherapy-responsive ones. The trials are biologically rational, operationally feasible, and have not been run. They should be. This is a preprint and has not yet been peer-reviewed. Companion paper: "Combinatorial completeness in cancer immunotherapy: a structural framework for addressing the seven failure modes of immune-mediated tumor control" (Paper 3 of this series).