The new form of IL-12 has been demonstrated to overcome the limitations of current treatments, presenting a safer and more effective therapy for cancer patients.
Cytokines are small proteins that facilitate communication between cells. They are major regulators of innate and adaptive immunity and have been used in cancer therapy, where these proteins drive anti-proliferative or pro-apoptotic activity.
Interleukin-12 (IL-12) is a pro-inflammatory cytokine that regulates T cells and natural killer cell responses, exerting anti-tumour effects against solid tumours. However, the clinical administration of IL-12 has been limited due to its short half-life, low efficacy, and dose-limiting systemic toxicity.
Reported in Science Immunology, Professor Peng Hua at the Institute of Biophysics of the Chinese Academy of Sciences, Professor Fu Yangxin at the University of Texas Southwestern Medical Center, and colleagues, formulated a new form of IL-12, called pro-IL-12, with low toxicity, tumour restriction, and high anti-tumour efficiency.
In this study, the researchers first constructed an IL-12-Fc fusion protein to extend the in vivo half-life of IL-12. Then, they proceeded to construct a pro-IL-12 with the functional site masked by selective natural IL-12 extracellular receptor-binding domains. This functional site could be unmasked by matrix metalloproteinases expressed by tumours, reactivating pro-IL-12. In mouse tumour models, treatment with pro-IL-12 induced profound anti-tumour efficacy and prolonged mouse survival. When compared to IL-12-Fc, the team’s developed pro-IL-12 displayed reduced toxicity and better control of established tumours.
Mechanistically, the research team found that the developed pro-IL-12 directly activated CD8+ T cells to release IFNƴ within the tumour microenvironment. When pro-IL-12 is used in combination with both tyrosine kinase inhibitors (TKI)-targeted therapy and immune checkpoint blockade (ICB) therapy, pro-IL-12 improved the therapeutic outcomes. This presents us with a new therapeutic regimen to reduce tumour resistance to current treatments.
As the newly developed pro-IL-12 proved more efficacious when combined with current treatment modalities and was able to reduce adverse effects, the study has not only presented a potentially safer therapy for cancer patients but also a platform for future anti-tumour pro-cytokine design. [APBN]
Source: Xue et al. (2022). A tumor-specific pro-IL-12 activates preexisting cytotoxic T cells to control established tumors. Science Immunology, 7(67), eabi6899.