Riboswitch-controlled IL-12 gene therapy reduces hepatocellular cancer in mice

Proinflammatory cytokine Tolerability
DOI: 10.3389/fimmu.2024.1360063 Publication Date: 2024-03-15T08:53:08Z
ABSTRACT
Hepatocellular carcinoma (HCC) and solid cancers with liver metastases are indications high unmet medical need. Interleukin-12 (IL-12) is a proinflammatory cytokine substantial anti-tumor properties, but its therapeutic potential has not been realized due to severe toxicity. Here, we show that orthotopic tumors in mice can be treated by targeting hepatocytes via systemic delivery of adeno-associated virus (AAV) vectors carrying the murine IL-12 gene. Controlled production was achieved vivo using tetracycline-inducible K19 riboswitch. AAV-mediated expression led STAT4 phosphorylation, interferon-γ (IFNγ) production, infiltration T cells and, ultimately, tumor regression. By detailed analyses efficacy tolerability healthy tumor-bearing animals, could define safe efficacious vector dose. As clinical candidate, characterized human (huIL-12) In mice, bioactive expressed dose-dependent manner induced tetracycline, suggesting tissue-specific AAV riboswitch-controlled highly potent cytokines as an attractive approach for vector-based cancer immunotherapy.
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