Research ArticleCancer

Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy

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Science Translational Medicine  26 Jun 2019:
Vol. 11, Issue 498, eaaw2614
DOI: 10.1126/scitranslmed.aaw2614

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Keeping it local

Cancer immunotherapy has greatly advanced in recent years, with a variety of promising approaches. Unfortunately, many patients still do not respond to the available therapeutics. Cytokine-based treatments have been proposed in the past but have not caught on because of the severe adverse effects associated with systemic cytokine exposure. To address this problem, Momin et al. fused antitumor cytokines to the collagen-binding protein lumican. Intratumoral injection of the resulting fusion proteins in mouse models of cancer effectively potentiated the effects of other immunotherapies and stimulated systemic antitumor immunity without detectable toxicity.

Abstract

The clinical application of cytokine therapies for cancer treatment remains limited due to severe adverse reactions and insufficient therapeutic effects. Although cytokine localization by intratumoral administration could address both issues, the rapid escape of soluble cytokines from the tumor invariably subverts this effort. We find that intratumoral administration of a cytokine fused to the collagen-binding protein lumican prolongs local retention and markedly reduces systemic exposure. Combining local administration of lumican-cytokine fusions with systemic immunotherapies (tumor-targeting antibody, checkpoint blockade, cancer vaccine, or T cell therapy) improves efficacy without exacerbating toxicity in syngeneic tumor models and the BrafV600E/Ptenfl/fl genetically engineered melanoma model. Curative abscopal effects on noncytokine-injected tumors were also observed as a result of a protective and systemic CD8+ T cell response primed by local therapy. Cytokine collagen-anchoring constitutes a facile, tumor-agnostic strategy to safely potentiate otherwise marginally effective systemic immunotherapies.

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