title: Assessing Immune-Related Adverse Events of Efficacious Combination Immunotherapies in Preclinical Models of Cancer.
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. Cancer Res; 76(18); 5288-301. ©2016 AACR.
authors: Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors: Jing
authors: J
authors: Liu
authors: Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors: Stephen J
authors: SJ
authors: Blake
authors: Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors: Heidi
authors: H
authors: Harjunpää
authors: The Walter and Eliza Hall Institute of Medical Research, Molecular Medicine Division, Melbourne, Australia. The Department of Experimental Medicine, University of Melbourne, Parkville, Victoria, Australia.
authors: Kirsten A
authors: KA
authors: Fairfax
authors: Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors: Michelle C R
authors: MC
authors: Yong
authors: Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors: Stacey
authors: S
authors: Allen
authors: Division of Oncology, Department of Medicine, Stanford University, Stanford, California.
authors: Holbrook E
authors: HE
authors: Kohrt
authors: Division of Cell Biology, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan.
authors: Kazuyoshi
authors: K
authors: Takeda
authors: Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia.
authors: Mark J
authors: MJ
authors: Smyth
authors: Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia. michele.teng@qimrberghofer.edu.au.
authors: Michele W L
authors: MW
authors: Teng
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000009:adverse effects; D045744:Cell Line, Tumor; D004167:Diphtheria Toxin; D004195:Disease Models, Animal; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors; D007167:Immunotherapy / Q000009:adverse effects* / Q000379:methods; D000074324:Ipilimumab; D008212:Lymphocyte Depletion / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental; D000077594:Nivolumab; D050378:T-Lymphocytes, Regulatory
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000074324:Ipilimumab; D000077594:Nivolumab