Background: Durability of response is the hallmark of immunotherapy but only a fraction of patients experience this prolonged benefit. Recent studies suggest more patients may benefit from combining agents with complementary immunological mechanisms. NKTR-214 is an engineered form of IL-2 that directly activates cytotoxic T cells by targeting the IL-2 receptor beta subunit and exhibits a pharmacokinetic profile that is more like an antibody than a cytokine. Anti-CTLA-4 and anti-PD1 are antibodies that block negative regulation of T cells. Here we show that combining either antibody with NKTR-214, provides significant tumor growth inhibition in resistant mouse models. Methods: For combination studies, BALB/c mice bearing established CT-26 (Colon Carcinoma) or EMT6 (Mammary Carcinoma) tumors were treated with single agent NKTR-214, murine anti-CTLA-4 antibody, murine anti-PD-1 or the two agents in combination. Results: NKTR-214 exhibits a plasma and tumor exposure that is 600-fold and 500-fold greater respectively, than an equivalent dose of the original IL-2 cytokine. The optimized PK profile allows q9d dosing schedule instead of bid; the latter being typical for cytokines. In both the EMT-6 and the CT-26 models, the combination of NKTR-214 with anti-CTLA-4 provided 10/12 and 8/12 tumor-free animals respectively, up to 40 days after the last dose and showed clear synergy compared to either agent alone. The combination with anti-PD1 was also synergistic and showed tumor regression in 5/10 animals. Single agent administration did not show any significant tumor growth inhibition in these models. The combinations were well tolerated with no body weight loss or other clinical signs. Conclusions: NKTR-214 directly stimulates cytotoxic T cells and is therefore complementary to the mechanism of checkpoint inhibition using antibodies. The favorable pharmacokinetics of NKTR-214 enables dosing schedules that are more like an antibody allowing convenient combination with other antibodies. Combining NKTR-214 mediated T cell activation with CTLA-4 or PD1 blockade is synergistic in murine models of cancer and holds the promise for durable responses in humans.