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

Jing Liu, Stephen J. Blake, Heidi Harjunpää, Kirsten A. Fairfax, Michelle C.R. Yong, Stacey Allen, Holbrook E. Kohrt, Kazuyoshi Takeda, Mark J. Smyth, Michele W.L. Teng

Research output: Contribution to journalArticlepeer-review

75 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5288-5301
Number of pages14
JournalCancer Research
Volume76
Issue number18
DOIs
Publication statusPublished or Issued - 15 Sept 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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