Li et al. showed that lipid nanoparticles containing self-replicating RNA expressing IL-12 (LNP-Rep_IL-12) induced efficient immunogenic cell death (ICD), activated innate immunity, and modulated immune cells. Single LNP-Rep_IL-12 injection elevated IL-12 and IFNγ serum levels, induced granulocyte and CD8+ T cell infiltration, and led to tumor control and long-term survival in multiple mouse models. Inhibition of CD8+ T cells or knocking out STING or Myd88 signaling diminished LNP-Rep_IL-12-mediated antitumor immunity. In bilateral or metastatic settings, LNP-Rep_IL-12 induced systemic immunity.
Contributed by Shishir Pant
ABSTRACT: 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 antitumor immunity. Here we describe self-replicating RNAs encapsulated in lipid nanoparticles (LNP), 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 interleukin (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 antitumor immunity. In several mouse models of cancer, a single intratumoral injection of LNP-replicons 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.
Author Info: (1) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA (2) Koch Institute for Integrative Cancer Research, Massachusetts Institute of T
Author Info: (1) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA (2) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA (3) Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA (4) Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA (5) Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA (6) Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA (7) Howard Hughes Medical Institute, Chevy Chase, MD, USA.
