Open AccessMultifunctional oncolytic nanoparticles deliver self-replicating IL-12 RNA to eliminate established tumors and prime systemic immunity
Author(s) -
Yingzhong Li,
Zhijun Su,
Weiliang Zhao,
Xinfu Zhang,
Noor Momin,
Chengxiang Zhang,
K. Dane Wittrup,
Yizhou Dong,
Darrell J. Irvine,
Ron Weiss
Publication year - 2020
Publication title -
nature cancer
Language(s) - English
Resource type - Journals
ISSN - 2662-1347
DOI - 10.1038/s43018-020-0095-6
Subject(s) - replicon , immune system , priming (agriculture) , cancer research , immunotherapy , immunity , cancer immunotherapy , immunology , systemic administration , biology , tumor microenvironment , cancer , medicine , in vivo , gene , botany , germination , biochemistry , microbiology and biotechnology , plasmid
Therapies that synergistically stimulate immunogenic cancer cell death (ICD), inflammation, and immune priming are of great interest for cancer immunotherapy. However, even multi-agent therapies often fail to trigger all of the steps necessary for self-sustaining anti-tumor immunity. Here we describe self-replicating RNAs encapsulated in lipid nanoparticles (LNP-replicons), which combine three key elements: (1) an LNP composition that potently promotes ICD, (2) RNA that stimulates danger sensors in transfected cells, and (3) RNA-encoded IL-12 for modulation of immune cells. Intratumoral administration of LNP-replicons led to high-level expression of IL-12, stimulation of a type I interferon response, and cancer cell ICD, resulting in a highly inflamed tumor microenvironment and priming of systemic anti-tumor immunity. In several mouse models of cancer, a single intratumoral injection of replicon-LNPs eradicated large established tumors, induced protective immune memory, and enabled regression of distal uninjected tumors. LNP-replicons are thus a promising multifunctional single-agent immunotherapeutic.