Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours
- 13 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Biomedical Engineering
- Vol. 4 (5), 531-543
- https://doi.org/10.1038/s41551-020-0549-2
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.Keywords
This publication has 51 references indexed in Scilit:
- IL-12 triggers a programmatic change in dysfunctional myeloid-derived cells within mouse tumorsJCI Insight, 2011
- A phase I trial of paclitaxel and trastuzumab in combination with interleukin-12 in patients with HER2/neu-expressing malignanciesMolecular Cancer Therapeutics, 2009
- Immunogenicity of the Hu14.18-IL2 Immunocytokine Molecule in Adults With Melanoma and Children With NeuroblastomaClinical Cancer Research, 2009
- CXC‐chemokine‐ligand‐10 gene therapy efficiently inhibits the growth of cervical carcinoma on the basis of its anti‐angiogenic and antiviral activityBiotechnology and Applied Biochemistry, 2009
- BrafV600E cooperates with Pten loss to induce metastatic melanomaNature Genetics, 2009
- Why are tumour blood vessels abnormal and why is it important to know?British Journal of Cancer, 2009
- Intratumoral injection of IL-12 plasmid DNA – results of a phase I/IB clinical trialCancer Gene Therapy, 2007
- Intratumoral Recombinant Human Interleukin-12 Administration in Head and Neck Squamous Cell Carcinoma Patients Modifies Locoregional Lymph Node Architecture and Induces Natural Killer Cell Infiltration in the Primary TumorClinical Cancer Research, 2005
- Tumor Cell Responses to IFNγ Affect Tumorigenicity and Response to IL-12 Therapy and AntiangiogenesisImmunity, 1998
- Interleukin-12: Role of Interferon-γ in IL-12 Adverse EffectsClinical Immunology and Immunopathology, 1997