Given that new immunotherapies in combination are displaying both efficacy and immune related adverse events (irAEs) in humans, there is a need to promptly develop a pre-clinical mouse model that can evaluate the therapeutic index (efficacy versus safety) of current and novel immunotherapies. We demonstrated that transient or 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. We showed that transient Treg depletion with DT in combination with anti-PD-1 or anti-TIM-3 monoclonal antibodies (mAbs) had a high therapeutic index compared to DT plus anti-CD137. While all three mAbs suppressed tumor growth, tumor rejection was more frequently observed in the DT plus anti-PD-1 or DT plus anti-TIM-3 combinations, depending on the tumor type, and these mice developed only mild irAEs. In contrast, mice treated with DT plus anti-CD137 developed severe irAEs characterized by infiltration of activated T cells into peripheral organs, liver toxicities and elevated levels of inflammatory cytokines, 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 the severity of irAEs in these mice without impacting on tumor growth. This model may now be used to pre-clinically assess the therapeutic indices of novel immunotherapy combinations to understand their mechanism of action and safety.
Citation Format: Jing Liu, Stephten J. Blake, Kirsten A. Fairfax, Michelle C.R. Yong, Stacey Allen, Mark J. Smyth, Michele W.L. Teng. A preclinical mouse model to assess antitumor efficacy and development of immune related adverse events (irAEs) following combination immunotherapies. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B122.
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