Mansurov and Ishihara et al. fused the A3 collagen-binding domain of VWF to IL-12 (CBD-IL-12) and compared its activity and safety with unmodified IL-12 in cold breast and melanoma tumor models. IV administration of CBD-IL-12 induced significant tumor regression and prolonged survival, with immunological memory. By accumulating rapidly in tumors, CBD-IL-12 increased intratumoral CD8+ effector T cells and IFNγ, and significantly altered the TME. In contrast, CBD-IL-12 was associated with lower circulating IFNγ and reduced indicators of toxicity. In large B16F10 tumors and two autochthonous models, CBD-IL-12 strongly synergized with CPI.
Contributed by Katherine Turner
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-gamma, 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.
Author Info: (1) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (2) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. juni@u
Author Info: (1) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (2) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. juni@uchicago.edu. (3) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (4) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (5) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. Committee on Immunology, University of Chicago, Chicago, IL, USA. (6) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (7) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (8) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (9) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (10) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. (11) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. Committee on Immunology, University of Chicago, Chicago, IL, USA. Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA. (12) Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA. jhubbell@uchicago.edu. Committee on Immunology, University of Chicago, Chicago, IL, USA. jhubbell@uchicago.edu.
