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Assessing immune-related adverse events of efficacious combination immunotherapies in preclinical models of cancer

Citation

Liu, J and Blake, SJ and Harjunpaa, H and Fairfax, KA and Yong, MC and Allen, S and Kohrt, HE and Takeda, K and Smyth, MJ and Teng, MW, Assessing immune-related adverse events of efficacious combination immunotherapies in preclinical models of cancer, Cancer Research, 76, (18) pp. 5288-5301. ISSN 0008-5472 (2016) [Refereed Article]

Copyright Statement

Copyright 2016 American Association for Cancer Research

DOI: doi:10.1158/0008-5472.CAN-16-0194

Abstract

New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAE) in humans. However, grade 3/4 irAEs occur in a high proportion, which can lead to discontinuation of treatment and can result in fatalities if not promptly treated. Prolonged T regulatory cell (Treg) depletion in tumor-bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of antitumor responses and severity of irAEs that can occur in ipilimumab/nivolumab-treated patients. In contrast, transient Treg depletion or anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily induced following treatment with additional immunomodulatory antibodies. Transient Treg depletion of DT in combination with anti-PD-1 or anti-TIM-3 monoclonal antibodies had a high therapeutic window compared with DT plus anti-CD137. In contrast, DT plus anti-CD137-treated mice developed severe irAEs similar to grade 3/4 clinical symptoms. These irAEs appeared because of an infiltration of activated proliferating effector T cells in the tissues producing IFNγ and TNF; however, TNF blockade decreased irAEs severity without impacting on tumor growth.

Item Details

Item Type:Refereed Article
Research Division:Biological Sciences
Research Group:Biochemistry and cell biology
Research Field:Cell development, proliferation and death
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Fairfax, KA (Dr Kirsten Fairfax)
ID Code:134798
Year Published:2016
Web of Science® Times Cited:48
Deposited By:Menzies Institute for Medical Research
Deposited On:2019-09-05
Last Modified:2019-10-11
Downloads:0

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