Negatively charged ligand-free RNA liposomes effectively trigger an antitumor immune response.

  • Major finding: Negatively charged ligand-free RNA liposomes effectively trigger an antitumor immune response.

  • Mechanism: RNA liposomes deliver antigens to dendritic cells and induce dendritic cell–mediated IFNα release.

  • Impact: Systemic delivery of RNA liposomes may be a broadly potent cancer immunotherapeutic approach.

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Strategies to develop cancer vaccines using dendritic cells (DC), which are very proficient antigen-presenting cells that trigger the immune response in lymphoid tissue upon early detection of pathogens, include the systemic delivery of antigen-encoding nucleic acids complexed with cationic liposomes. However, the delivery of positively charged RNA liposomes (RNA-LPX), which exhibited greater in vitro transfection efficiency than negatively charged RNA-LPXes, failed to induce significant antitumor responses. Using the three most common lipid formulations, Kranz, Diken, and colleagues established a panel of luciferase (Luc) RNA-LPXes of different net charges by altering lipid:RNA ratios to ascertain the effects of RNA-LPX net charge on targeting DCs and evoking antitumor immunity. Intravenous delivery of Luc RNA-LPXes revealed that a shift from a net positive to a net negative charge resulted in a shift from preferential targeting of the lungs to preferential targeting of the spleen. Because in vivo transfection efficiency decreased with increasingly negative net charges, RNA-LPXes with a moderately negative net charge, which effectively targeted antigen-presenting cells (APC) such as DCs, were used for the remaining studies. Systemic delivery of RNA-LPXes encoding a pathogenic antigen or ovalbumin induced APC maturation, increased toll-like receptor 7 (TLR7)–mediated production of IFNα by DCs, and enhanced the expansion of APCs and activated antigen-specific T cells. Consistent with these findings, immunization with ovalbumin RNA-LPX encoding various types of tumor antigens cleared colon cancer and melanoma metastases, caused tumor regression, and prevented tumor regrowth in tumor-bearing mice. Similarly, in a phase I trial, three patients with melanoma who were treated with RNA-LPX vaccines encoding four tumor antigens exhibited increased IFNα and an enhanced activated T-cell response in a dose-dependent manner. Together, these findings identify an antiviral-like mechanism by which RNA liposomes concomitantly promote potent adaptive and innate immune responses, and provide evidence for the clinical activity of a systemically delivered nucleic acid–liposomal vaccine.

Kranz LM, Diken M, Haas H, Kreiter S, Loquai C, Reuter KC, et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 2016;534:396–401.

Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.