Background NKTR-214 is an immunotherapeutic drug that exerts its biological activity by binding and activating the interleukin-2 (IL-2) receptor beta subunit (IL-2Rb), thereby causing expansion of memory effector T cells in the tumor. NKTR-214 consists of 4-6 releasable polyethylene glycol (PEG) chains conjugated to IL-2 at a defined region within the protein. In vivo, some of these PEG chains slowly release to generate active IL-2 conjugates. The location of these PEG chains on IL-2 interferes with its interaction on the IL-2 receptor alpha (IL-2Ra), responsible for activating undesirable Treg cells in tumor. In vivo, the receptor bias markedly increases the ratio of tumor killing CD8 T cells to Treg cells in tumors, while simultaneously leading to high and sustained tumor exposure. NKTR-214 showed marked single agent efficacy in aggressive murine tumors, and synergy with anti-CTLA-4, producing durable responses. Here, we examine the efficacy and mechanism of NKTR-214 combined with anti-PD-1 in murine tumor models.