A hybrid fever therapy for increased tumor selectivity

Lipopolysaccharide (LPS), mediator of the Coley and Shwartzman fever therapies, is a potent endotoxin capable of inducing sepsis at moderate intravenous doses, which currently limits its experimental and clinical use. By exploiting elevated G-CSF concentrations and neutrophil numbers within tumors, it may be possible to selectively trigger a sepsis-like syndrome in malignant tissues using only moderate hyperthermia and low-dose LPS, leaving normal organs unaffected. Analogous to the organ failure that can result from severe sepsis, repeated application of the proposed procedure could lead to tumor necrosis and regression. Biomarkers including heat shock proteins and circulating endothelial cells, and intravital microscopy of intravascular NETs, microthrombi, and bleeding in tumors can be used to test predicted consequences of this therapy. The two components of this hybrid approach, hyperthermia and acute but mild endotoxemia, could provide a tumor-specific therapeutic modality with relatively mild side effects, and therefore permit repeated application over an extended treatment period.