Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established ‘immunologically cold’ murine tumours

• Published in: Nature biomedical engineering Vol. 4; no. 5; pp. 531 - 543
• Main Authors: Mansurov, Aslan, Ishihara, Jun, Hosseinchi, Peyman, Potin, Lambert, Marchell, Tiffany M., Ishihara, Ako, Williford, John-Michael, Alpar, Aaron T., Raczy, Michal M., Gray, Laura T., Swartz, Melody A., Hubbell, Jeffrey A.
• Format: Journal Article
• Language: English
• Published: 13.04.2020
• ISSN: 2157-846X
• DOI: 10.1038/s41551-020-0549-2

Checkpoint inhibitor (CPI) immunotherapy has achieved remarkable clinical success, yet its efficacy in ‘immunologically cold’ tumours has been modest. Interleukin (IL)-12 is a powerful cytokine that activates the innate and adaptive arms of the immune system, yet its administration has been associated with immune-related adverse events. Here, we show that the intravenous administration of a collagen-binding domain fused to IL-12 (CBD–IL-12) in mice bearing aggressive murine tumours accumulates in the tumour stroma, owing to exposed collagen in the disordered tumour vasculature. In comparison with the administration of unmodified IL-12, CBD–IL-12 induced sustained intratumoral levels of interferon-γ, markedly reduced its systemic levels as well as organ damage, and led to superior anticancer efficacy, eliciting complete regression of CPI-unresponsive breast tumours. Furthermore, CBD–IL-12 potently synergized with CPI to eradicate large established melanoma, induced antigen-specific immunological memory, and controlled tumour growth in a genetically engineered mouse model of melanoma. CBD–IL-12 may potentiate CPI immunotherapy for immunologically cold tumours.