OX40-targeted immune agonist antibodies induce potent antitumor immune responses without inducing liver damage in mice.

Despite promising preclinical and clinical data demonstrating that immune agonist antibody immunotherapies (IAAs) such as αOX40 induce strong antitumor immune responses, clinical translation has been significantly hampered by the propensity of some IAAs to induce dose-limiting and sometimes life-threatening immunotoxicities such as cytokine release syndrome and hepatotoxicity. For example, in a recent study αOX40 was shown to induce significant liver damage in mice by inducing the pyroptosis of liver natural killer T cells (NKT) cells. Surprisingly; however, given these previous reports, αOX40 treatment in our hands did not induce NKT cell pyroptosis or liver damage. We investigated numerous potential confounding factors including age, sex, tumor burden, dosing strategy, and the gut microbiota, which could have explained this discrepancy with the previous study. In none of these experiments did we find that αOX40 induced any more than very mild inflammation in the liver. Our study therefore suggests that, preclinically, αOX40 is a safe and effective immunotherapy and further studies into the clinical benefit of αOX40 are warranted.