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Sci Transl Med. 2019 Jun 26;11(498). pii: eaaw2614. doi: 10.1126/scitranslmed.aaw2614.

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

Momin N1,2, Mehta NK1,2, Bennett NR1, Ma L1,3, Palmeri JR1,4, Chinn MM1,2, Lutz EA1,2, Kang B1,2, Irvine DJ1,2,3,5,6, Spranger S1,7, Wittrup KD8,2,4.

Author information

1
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
2
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
3
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
4
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
5
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
6
Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
7
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
8
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA. wittrup@mit.edu.

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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