Issues

Despite the major improvement to cancer outcomes with the development of checkpoint inhibitors, many patients will not respond or will develop resistance to these therapies. As strategies to dually target pathways that are complementary against immunoregulation may relieve these issues, Muik and colleagues generated a bispecific antibody targeting both the PD-1/PD-L1 axis and 4-1BB costimulation (DuoBody-PD-L1×4-1BB, GEN1046), which showed activation of antitumor immunity that was mediated by T-cell response and was superior in mouse models to current clinically approved PD-(L)1 inhibitors. GEN1046 was further tested in a first-in-human phase I/IIa dose-escalation study of 61 patients with advanced, heavily pretreated, refractory solid tumors and demonstrated safety as well as early clinical activity, suggesting that this developed bispecific antibody could be used in patients with checkpoint inhibitor–relapsed or refractory disease. For more information, see the article by Muik and colleagues on page 1248.