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

doi:10.1016/j.isci.2024.108836

Nanosphere pharmacodynamics improves safety of immunostimulatory cytokine therapy

iScience. 2024 Jan 9;27(2):108836. doi: 10.1016/j.isci.2024.108836. eCollection 2024 Feb 16.

Authors

Ryan A Lacinski¹, Sebastian A Dziadowicz^{2

3}, Amanda Stewart¹, Edwin Chaharbakhshi¹, Halima Akhter^{2

3}, John J Pisquiy¹, Jack H Victory¹, Joshua B Hardham¹, Claude Chew⁴, Alyson Prorock⁵, Yongde Bao⁵, Katia Sol-Church⁵, Gerald R Hobbs¹, Edwin Klein⁶, Michael A Nalesnik⁷, Gangqing Hu^{2

3}, Ana de Oliveira⁸, Stell P Santiago⁹, Brock A Lindsey¹⁰

Affiliations

¹ Department of Orthopaedics, West Virginia University School of Medicine, Morgantown, WV 26505, USA.
² Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26505, USA.
³ Bioinformatics Core, West Virginia University School of Medicine, Morgantown, WV 26505, USA.
⁴ Advanced Technology Cores, Baylor College of Medicine, Houston, TX 77030, USA.
⁵ Genome Analysis & Technology Core, University of Virginia School of Medicine, Charlottesville, VA 22904, USA.
⁶ Division of Laboratory Animal Resources, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
⁷ Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15260, USA.
⁸ Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA 22904, USA.
⁹ Department of Pathology, West Virginia University School of Medicine, Morgantown, WV 26505, USA.
¹⁰ Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Abstract

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.

Keywords: Biological sciences; Drug dispensing; Health sciences; Immunology; Natural sciences; Pharmaceutical compounds formulation; Pharmaceutical science; Pharmacology.

Abstract

Grants and funding