Low-dose vaccinia virus-mediated cytokine gene therapy of glioma

Area of Science:

• Oncolytic virotherapy
• Immunotherapy
• Gene therapy

Background:

• Recombinant viruses can stimulate anti-tumor immune responses by producing cytokines within tumors.
• Investigating the efficacy and safety of recombinant vaccinia viruses (rVVs) engineered to express cytokine genes is crucial for cancer treatment development.

Purpose of the Study:

• To evaluate the in vivo antitumor efficacy and safety of attenuated rVV strains expressing murine interleukin-2 (IL-2), IL-12, or both IL-2 and IL-12.
• To assess the impact of different rVV doses on tumor inhibition and cytokine toxicity.

Main Methods:

• Athymic nude mice bearing subcutaneous C6 glioma xenografts were treated with various doses of rVV constructs (rVV-mIL-2, rVV-mIL-12, rVV-2-12).
• Gene expression, tumor growth, immune cell populations (natural killer T cells), and cytokine levels (interferon-gamma, tumor necrosis factor-alpha) were analyzed.
• Safety was assessed by monitoring for signs of cytokine toxicity at different rVV doses.

Main Results:

• Significant tumor inhibition was observed across a range of rVV doses (10^2 to 10^7 PFU), with no dose-dependency for rVV-mIL-2 and rVV-mIL-12.
• High doses of rVVs induced cytokine toxicity, which was significantly reduced at lower doses (10^2 to 10^3 PFU).
• rVV-mIL-12 treatment correlated with increased splenic natural killer T cells and elevated local interferon-gamma and tumor necrosis factor-alpha, linked to tumor growth arrest.

Conclusions:

• Attenuated recombinant vaccinia viruses expressing cytokine genes demonstrate significant antitumor activity against gliomas in mice.
• Low-dose administration of these rVVs offers a potentially safer approach by reducing toxicity while preserving therapeutic efficacy.
• These findings support the potential of low-dose, cytokine-expressing rVVs as effective vectors for cancer immunotherapy.