Nanosphere pharmacodynamics improves safety of immunostimulatory cytokine therapy
Ryan A. Lacinski,
Sebastian A. Dziadowicz,
Amanda Stewart,
Edwin Chaharbakhshi,
Halima Akhter,
John J. Pisquiy,
Jack H. Victory,
Joshua B. Hardham,
Claude Chew,
Alyson Prorock,
Yongde Bao,
Katia Sol-Church,
Gerald R. Hobbs,
Edwin Klein,
Michael A. Nalesnik,
Gangqing Hu,
Ana de Oliveira,
Stell P. Santiago,
Brock A. Lindsey
Affiliations
Ryan A. Lacinski
Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
Sebastian A. Dziadowicz
Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26505, USA; Bioinformatics Core, West Virginia University School of Medicine, Morgantown, WV 26505, USA
Amanda Stewart
Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
Edwin Chaharbakhshi
Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
Halima Akhter
Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26505, USA; Bioinformatics Core, West Virginia University School of Medicine, Morgantown, WV 26505, USA
John J. Pisquiy
Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
Jack H. Victory
Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
Joshua B. Hardham
Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
Claude Chew
Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA
Alyson Prorock
Genome Analysis & Technology Core, University of Virginia School of Medicine, Charlottesville, VA 22904, USA
Yongde Bao
Genome Analysis & Technology Core, University of Virginia School of Medicine, Charlottesville, VA 22904, USA
Katia Sol-Church
Genome Analysis & Technology Core, University of Virginia School of Medicine, Charlottesville, VA 22904, USA
Gerald R. Hobbs
Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA
Edwin Klein
Division of Laboratory Animal Resources, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
Michael A. Nalesnik
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15260, USA
Gangqing Hu
Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26505, USA; Bioinformatics Core, West Virginia University School of Medicine, Morgantown, WV 26505, USA
Ana de Oliveira
Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA
Stell P. Santiago
Department of Pathology, West Virginia University School of Medicine, Morgantown, WV 26505, USA
Brock A. Lindsey
Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Corresponding author
Summary: Systemic administration of interleukin (IL)-12 induces potent anti-tumor immune responses in preclinical cancer models through the systemic activation of effector immune cells and release of proinflammatory cytokines. IL-12-loaded PLGA nanospheres (IL12ns) are hypothesized to improve therapeutic efficacy and thwart unwanted side effects observed in previous human clinical trials. Through the investigation of peripheral blood and local tissue immune responses in healthy BALB/c mice, the immune-protective pharmacodynamics of IL12ns were suggested. Nanospheres increased pro-inflammatory plasma cytokines/chemokines (IFN-γ, IL-6, TNF-α, and CXCL10) without inducing maladaptive transcriptomic signatures in circulating peripheral immune cells. Gene expression profiling revealed activation of pro-inflammatory signaling pathways in systemic tissues, the likely source of these effector cytokines. These data support that nanosphere pharmacodynamics, including shielding IL-12 from circulating immune cells, depositing peripherally in systemic immune tissues, and then slowly eluting bioactive cytokine, thereafter, are essential to safe immunostimulatory therapy.