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

journal contribution
posted on 2023-05-20, 06:56 authored by Liu, J, Blake, SJ, Harjunpaa, H, Kirsten FairfaxKirsten Fairfax, Yong, MC, Allen, S, Kohrt, HE, Takeda, K, Smyth, MJ, Teng, MW
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.


Publication title

Cancer Research










Menzies Institute for Medical Research


Amer Assoc Cancer Research

Place of publication

615 Chestnut St, 17Th Floor, Philadelphia, USA, Pa, 19106-4404

Rights statement

Copyright 2016 American Association for Cancer Research

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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