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Riboswitch-controlled IL-12 gene therapy reduces hepatocellular cancer in mice
Matthias J Düchs1, Ramona F Kratzer2, Pablo Vieyra-Garcia3
1Research Beyond Borders, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Abstract:
Hepatocellular carcinoma (HCC) and solid cancers with liver metastases are indications with high unmet medical need. Interleukin-12 (IL-12) is a proinflammatory cytokine with substantial anti-tumor properties, but its therapeutic potential has not been realized due to severe toxicity. Here, we show that orthotopic liver 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 cytokine production was achieved in vivo by using the tetracycline-inducible K19 riboswitch. AAV-mediated expression of IL-12 led to STAT4 phosphorylation, interferon-γ (IFNγ) production, infiltration of T cells and, ultimately, tumor regression. By detailed analyses of efficacy and tolerability in healthy and tumor-bearing animals, we could define a safe and efficacious vector dose. As a potential clinical candidate, we characterized vectors carrying the human IL-12 (huIL-12) gene. In mice, bioactive human IL-12 was expressed in a vector dose-dependent manner and could be induced by tetracycline, suggesting tissue-specific AAV vectors with riboswitch-controlled expression of highly potent proinflammatory cytokines as an attractive approach for vector-based cancer immunotherapy.
Insights
Hepatocellular carcinoma and liver metastases pose significant challenges. Researchers developed a novel adeno-associated virus (AAV) gene therapy to safely deliver Interleukin-12 (IL-12) for effective cancer treatment.
Area of Science:
- Oncology
- Gene Therapy
- Immunology
Background:
- Hepatocellular carcinoma (HCC) and liver metastases represent significant unmet medical needs.
- Interleukin-12 (IL-12) exhibits potent anti-tumor properties but is limited by severe toxicity.
- Adeno-associated virus (AAV) vectors offer potential for targeted gene delivery.
Purpose of the Study:
- To evaluate the efficacy and safety of AAV-mediated IL-12 gene delivery for treating liver tumors.
- To establish controlled cytokine production using a tetracycline-inducible riboswitch system.
- To assess the therapeutic potential of AAV-huIL-12 as a clinical candidate.
Main Methods:
- Systemic delivery of AAV vectors carrying murine or human IL-12 genes to orthotopic liver tumors in mice.
- Utilized a tetracycline-inducible K19 riboswitch for controlled IL-12 expression.
- Analyzed STAT4 phosphorylation, interferon-γ (IFNγ) production, T cell infiltration, tumor regression, and vector tolerability.
Main Results:
- AAV-mediated IL-12 expression successfully induced anti-tumor immune responses, including STAT4 phosphorylation and IFNγ production.
- Significant tumor regression was observed in treated mice.
- A safe and efficacious vector dose was determined through detailed efficacy and tolerability analyses.
- Bioactive human IL-12 expression was achieved in a dose-dependent and tetracycline-inducible manner.
Conclusions:
- Tissue-specific AAV vectors with riboswitch-controlled expression provide a safe and effective strategy for delivering potent proinflammatory cytokines.
- This approach holds promise for advancing vector-based cancer immunotherapy for liver malignancies.
- AAV-mediated IL-12 gene therapy represents an attractive platform for treating difficult-to-treat liver cancers.
