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

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Title: Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours
Authors: Mansurov, A
Ishihara, J
Hosseinchi, P
Potin, L
Marchell, TM
Ishihara, A
Williford, J-M
Alpar, AT
Raczy, MM
Gray, LT
Swartz, MA
Hubbell, JA
Item Type: Journal Article
Abstract: 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.
Issue Date: May-2020
Date of Acceptance: 12-Mar-2020
URI: http://hdl.handle.net/10044/1/83774
DOI: 10.1038/s41551-020-0549-2
ISSN: 2157-846X
Publisher: Nature Research
Start Page: 531
End Page: 543
Journal / Book Title: Nature Biomedical Engineering
Volume: 4
Issue: 5
Copyright Statement: © The Author(s), under exclusive licence to Springer Nature Limited 2020. The final publication is available at Springer via https://doi.org/10.1038/s41551-020-0549-2
Publication Status: Published
Online Publication Date: 2020-04-13
Appears in Collections:Bioengineering