"Designer cytokines" targeting the tumor vasculature-think global and act local.

Thomas Kammertoens,Matthias Leisegang,Josephine Kemna

doi:10.15252/emmm.201911801

Abstract

Tumor necrosis factor (TNF) was discovered in 1975 as a lipopolysaccharide-induced serum factor that causes necrosis of tumors (Carswell etal, 1975). It was later found that TNF and cachectin, a factor causing wasting disease, were one and the same molecule (Beutler etal, 1985). Studies on the inflammatory activity of TNF have been translated into clinical success, namely blocking antibodies used to suppress autoimmune diseases. Research on TNF anti-tumor activity, in contrast, has not yet resulted in a therapeutic breakthrough. This may change, based on a study by Huyghe etal (2020) describing novel "designer cytokines" (TNFand interferon-γ) that increase local activity by targeting the CD13-positive tumor vasculature, while simultaneously lowering the binding affinity to the respective cytokine receptor, thereby reducing off-target effects on normal cells.

Highlights

Tumor necrosis factor (TNF) was discovered in 1975 as a lipopolysaccharideinduced serum factor that causes necrosis of tumors (Carswell et al, 1975)
The anti-tumor effects of TNF and IFNc on activated tumor vasculature are probably the reason why immunotherapy using T cells can destroy solid tumors that are refractory to cytotoxic therapies (Kammertoens et al, 2017)
Because anti-tumor effects of TNF and IFNc had been observed in pre-clinical models, both cytokines were tested in the clinic when recombinant proteins became available

Summary

Introduction

Tumor necrosis factor (TNF) was discovered in 1975 as a lipopolysaccharideinduced serum factor that causes necrosis of tumors (Carswell et al, 1975). The anti-tumor effects of TNF and IFNc on activated tumor vasculature are probably the reason why immunotherapy using T cells can destroy solid tumors that are refractory to cytotoxic therapies (Kammertoens et al, 2017).

Results

Conclusion