抄録
After many years of trying to harness the immune system to fight cancer, recent approvals of ipilimumab and nivolumab, as well as encouraging data emerging from clinical trials, are transforming the way cancer is being treated. However, despite amazing clinical responses, stimulating the immune system either by taking the breaks off of immune inhibitory pathways (ie, anti-CTLA4 or -PD1 antagonists) or hitting the gas with immunostimulatory pathways (anti-CD137 or CD40 agonists) has led to immune-related adverse events (irAEs) in the clinic, which can be serious or fatal. These irAEs are related to the mechanism of action of these agents, resulting in T-cell inflammatory infiltrations in tissues and increases in systemic inflammatory cytokines. This presentation reviews the nonclinical safety assessment for ipilimumab (Yervoy) a fully human monoclonal antibody inhibitor of CTLA4 (CD152), a receptor expressed on T-cells following activation. Ipilimumab potentiates T cell responses by blocking the inhibitory modulation of T-cell activation promoted by the interaction of CTLA4 with CD80/86 on antigen presenting cells. The unique challenges with regards to monitoring for immune stimulation and its potential to induce adverse consequences in the nonclinical studies conducted in monkeys and with human tissues/cells in vitro and their translation to the clinic will be discussed.
