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

New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAEs) 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 anti-tumor 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 (mAbs) had a high therapeutic window compared to DT plus anti-CD137. In contrast, DT plus anti-CD137 treated mice ddeveloped severe irAEs similar to grade 3/4 clinical symptoms. These irAEs appeared due to 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.