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.
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We thank T. Gajewski (University of Chicago) for sharing Tyr:creER+ LSL-BrafV600E Ptenfl/fl and Tyr:creER+ LSL-BrafV600E Ptenfl/fl Ctnnb1STA mice; A. Solanki for assistance with tail vein injections; S. Gomes for assistance with experiments; T. Li for assistance with histology analysis; staff at the Human Tissue Resource Center of the University of Chicago for assistance with organ sectioning; and D. Leclerc (University of Chicago Flow Cytometry Core) for assistance with Luminex assays.
J.I., A.I., M.A.S. and J.A.H. are inventors on U.S. Provisional Patent applications 62/638,520, 28/984,351 and 62/727,156. J.I., A.I., M.A.S. and J.A.H. are founders and shareholders in Arrow Immune Inc., which is developing the technology presented in this report, and M.A.S. and J.A.H. have leadership roles in that company. The other authors declare no competing interests.
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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 4, 531–543 (2020). https://doi.org/10.1038/s41551-020-0549-2
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