iScience (Feb 2024)

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

Journal volume & issue
Vol. 27, no. 2
p. 108836

Abstract

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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.

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