Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours
Aslan Mansurov, Jun Ishihara, Peyman Hosseinchi, Lambert Potin, Tiffany M. Marchell, Ako Ishihara, John-Michael Williford, Aaron T. Alpar, Michal M. Raczy, Laura T. Gray, Melody A. Swartz & Jeffrey A. Hubbell
Checkpoint-inhibitor (CPI) immunotherapy has achieved remarkable clinical success, yet its efficacy in ‘immunologically cold’ tumours has been modest. Interleukin-12 (IL-12) is a powerful cytokine that activates the innate and adaptive arms of the immune system; however, the administration of IL-12 has been associated with immune-related adverse events. Here we show that, after intravenous administration of a collagen-binding domain fused to IL-12 (CBD–IL-12) in mice bearing aggressive mouse tumours, CBD–IL-12 accumulates in the tumour stroma due to exposed collagen in the disordered tumour vasculature. In comparison with the administration of unmodified IL-12, CBD–IL-12 induced sustained intratumoural levels of interferon-γ, substantially reduced its systemic levels as well as organ damage and provided superior anticancer efficacy, eliciting complete regression of CPI-unresponsive breast tumours. Furthermore, CBD–IL-12 potently synergized with CPI to eradicate large established melanomas, 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.
Reference: Mansurov, A., Ishihara, J., Hosseinchi, P. et al. Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours. Nat Biomed Eng (2020). Retrieved from https://www.nature.com