Uncovering first molecular mechanisms of secondary resistance against PD-1 blockade

Checkpoint inhibition by anti-PD-1 antibodies alone or in combination with CTLA-4 blockers is the new paradigm in the treatment of metastatic melanoma (1,2). Response rates are high with about 40% in anti-PD-1 monotherapy and about 60% in combination with anti-CTLA-4 inhibitors (3). Initially, responses were assumed to be durable, but soon it became evident that even deeply responding patients with completely decreased metastases bear the potential to relapse even under continuously ongoing therapy (4,5). The molecular mechanisms of this acquired resistance remained unclear until now, when Zaretsky and coworkers from the group of Antoni Ribas succeeded to unravel some first molecular mechanisms helping to understand this complex clinical situation (6)