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.