Background: IL-10 has anti-inflammatory activity and stimulates the cytotoxicity and proliferation of CD8+ T cells at higher concentrations. IL-10 receptors and PD1 are expressed on activated CD8 T cells, providing a rationale for combining AM0010 and an anti-PD1. The efficacy and safety profile for AM0010 alone was established in poor to intermediate risk RCC pts treated in 3^rdLOT. Objective responses were observed in 4 of 15 pts with RCC. In the dose escalation of AM0010 plus pembrolizumab, 4 of 8 patients had an objective response. The mPFS was 16.7 months and the mOS has not been reached, median follow up (mFU) is 19.3 mo. Methods: In this Phase 1b, 29 pts. with metastatic RCC were enrolled until Nov. 18 2016 on AM0010 (10 ug/kg daily SC) and nivolumab (3mg/kg, q2wk IV). 2 had favorable, 20 had intermediate and 4 had poor IMDC risk (3 were not available). Pts. had a median of 1 prior therapy (range 1-3). All pts. had received a VEGFR-TKI. Tumor responses were assessed with irRC. Immune responses were evaluated by serum cytokines, activation of blood derived T cells and peripheral T cell clonality. Results: AMO010 plus nivolumab was well tolerated. TrAEs were reversible. There were no autoimmune colitis, pneumonitis, or endocrine disorders. 14 patients had at least 1 G3/4 TrAE, including anemia (9), thrombocytopenia (5), hypertriglyceridaemia (4). 2 pts had a reversible cytokine release syndrome with splenomegaly and increased immune mediated red blood cell phagocytosis most likely precipitated by T-cell activation, as both pts had tumor responses. As of Jan 31 2017, partial responses (PR) were observed in 8 of 26 evaluable pts (31%). An additional 13 of 26 pts had stable disease (41%), 7 pts had tumor reductions of more than 30%. The mPFS and mOS has not been reached with a mFU of 5.2 mo. (range 0.3-10.3). AM0010 + anti-PD1 increased Th1 cytokines in the serum while decreasing TGFb, an expansion of proliferating PD1+ Lag3+ activated CD8 T cells and de-novo oligoclonal expansion of T cell clones in the blood. Conclusions: AM0010 in combination with nivolumab is well-tolerated in RCC pts. The efficacy and the observed CD8 T cell activation is promising and encourages the continued study of AM0010 in combination with nivolumab. Clinical trial information: NCT02009449