Background: IL-10 has anti-inflammatory properties but stimulates the cytotoxicity and proliferation of CD8 T cells. The observation that T cell receptor mediated activation induces the expression of IL-10 receptors and PD1 on CD8 T cells, provides the mechanistic rationale for combining AM0010 and anti-PD1 in the clinic. Tolerability and anti-tumor activity of AM0010 alone was established in the ongoing phase 1 study. Objective responses were observed in pts with uveal melanoma, cutaneous T cell lymphoma and in 4 of 15 pts with RCC. Methods: Pts with advanced melanoma, RCC or NSCLC were treated with AM0010 (daily SC) and Pembrolizumab (q3wk IV). Tumor responses were monitored following irRC. Immune responses were measured by analysis of serum cytokines, activation of blood derived T cells, peripheral T cell clonality and immunohistochemistry of tumor infiltrating CD8 T cells. Results: In 19 pts, AM0010 10 mg/kg (n=13) or 20 mg/kg (n=6) in combination with anti-PD1 (2mg/kg) was well tolerated (observation period 10-15 months). All TrAEs were transient and DLTs or TrAEs leading to study discontinuation were not observed. There was no colitis, pneumonitis, or endocrine disruptions. G3/4 TrAEs were observed in 7 of 19 pts and included pruritus (1), anemia (3), thrombocytopenia (3) and malaise (1). Objective responses (PR/CR) were observed in 4 of 8 RCC pts, 2 of 5 NSCLC pts and 2 of 6 melanoma pts. 2 additional melanoma pts had tumor increase followed by decrease (pseudoprogression). AM0010 / anti-PD1 increased Th1 cytokines (IL-18, IFNg, IL-7) and the number and proliferation of PD1+ activated CD8 T cells while decreasing the proliferation of FoxP3+ Tregs and TGFb in the blood. AM0010 / anti-PD1 induced de-novo oligoclonal expansion of T cell clones in the blood without affecting total lymphocyte counts. AM0010 / anti-PD1 increased the number of tumor infiltrating Granzyme+ PD1+ CD8+ T cells in tumor biopsies of treated patients. Conclusions: AM0010 in combination with anti-PD1 is well-tolerated. The clinical activity and the observed CD8 T cell activation encourages the continued exploration of AM0010 in combination with anti-PD1. Clinical trial information: NCT02009449