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


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.

SUBMITTER: Momin N 

PROVIDER: S-EPMC7811803 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Momin Noor N   Mehta Naveen K NK   Bennett Nitasha R NR   Ma Leyuan L   Palmeri Joseph R JR   Chinn Magnolia M MM   Lutz Emi A EA   Kang Byong B   Irvine Darrell J DJ   Spranger Stefani S   Wittrup K Dane KD  

Science translational medicine 20190601 498


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. Combi  ...[more]

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