Background: TAK-659 is a highly potent, reversible inhibitor of spleen tyrosine kinase (SYK) and fms related tyrosine kinase 3 (FLT3) that is being tested in combination with nivolumab in patients with advanced solid tumors (NCT02834247). NKTR-214, a CD-122-biased agonist that targets the IL-2 pathway, provides sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) to preferentially activate and expand NK and effector CD8+ T cells over T-regulatory cells in the tumor microenvironment, and is currently in multiple Phase I and II clinical trials in combination with checkpoint inhibitors (NCT02983045, NCT03138889). Treatment with TAK-659 in pre-clinical models resulted in a decrease in MDSCs and B220+ B-cells suggesting an immunomodulatory response, and the combination with anti-PD-1 therapy in pre-clinical in vivo models resulted in increased anti-tumor activity and durable complete responses. NKTR-214 monotherapy increases newly proliferative CD8+ T cells in tumors, increases cell surface PD-1 on immune cells and PD-L1 on tumor cells, and the combination with anti-PD-1 therapy shows marked efficacy in mouse syngeneic models. Methods: Here we explored the pre-clinical combination of TAK-659 with NKTR-214 in the presence or absence of anti-PD-1 therapy in multiple syngeneic tumor models. Results: TAK-659 in combination with NKTR-214 with or without anti-PD-1 therapy resulted in significant antitumor activity and durable complete tumor regressions. In the CT-26 murine colon cancer model, the TAK-659 + NKTR-214 or the triple combination with anti-PD-1 therapy resulted in 9 out of 10 mice having a maintained complete response (CR) 55 days post the end of treatment, versus 1 CR for TAK-659 or anti-PD-1 single agents, and none for NKTR-214 single agent. Complete responders, left untreated and re-challenged with another inoculation of tumor cells, did not form tumors, suggesting a potential immune memory. Conclusions: NKTR-214, TAK-659 and anti-PD-1 therapy bring together complementary non-overlapping mechanisms that create a promising potential therapy, supporting the rationale for examining the clinical combination.