Neo-Coley v2: A Unified Framework for Combinatorial PAMP Immunotherapy with Sustained Fever-Range Thermal Stress in Cancer

William Coley's bacterial cancer immunotherapy (1891–1936) reported durable response rates substantially higher than modern checkpoint inhibitor monotherapy in refractory disease, yet modern replication attempts (Karbach 2012; SYNB1891; OK-432; MBVax) have produced confirmed target engagement without durable regressions. This position paper articulates a convergent thesis for the gap: durable response requires four conditions in combination — combinatorial PAMP activation across multiple innate immune sensors (TLR2/3/4/7/8/9 and STING); sustained fever-range thermal stress (39–40°C) as the dosing endpoint rather than a side effect; multi-month treatment duration; and preservation of host immune function. Five developments since 2018 are integrated: personalized neoantigen mRNA vaccines, computational modeling of PAMP synergy, biomarker-based patient selection, scheduling informed by direct clinical experience, and the molecular case for fever as immune orchestrator (HSP90-α4 integrin trafficking, IL-6 trans-signaling, HSP-mediated antigen cross-presentation). Three implementation options are surveyed: whole bacterial preparations, live attenuated vaccine pathogens, and defined synthetic multi-PAMP cocktails using FDA-approved or clinical-stage agonists. A modular protocol design suitable as the basis of an investigator-initiated trial is specified, with an optional Component F leveraging multi-recall mRNA-LNP redirection (tetanus toxoid, SARS-CoV-2 spike epitopes). Sixteen empirical predictions and a decisive falsifier are articulated. The framework incorporates direct feedback from Professor Uwe Hobohm (THM University Giessen, retired) and is offered for testing, modification, or refutation.