Background: PD-1/B7-H1 (PD-L1) axis blockade can reinvigorate T cells, and overcome tumor immune evasion of multiple tumor types. AMP-224 is the first recombinant B7-DC-Fc fusion protein tested in patients that binds to and modulates the PD-1 axis through a unique MOA. The MoA hypothesis for AMP-224 is depletion of PD-1high expressing T-cells representing exhausted effector cells. Subsequent replenishment of the T-cell pool with functional T-cells may restore immune function. Methods: Patients with advanced solid tumors received low dose CTX on Day 0, followed by AMP-224 (IV infusion) on Days 1 and 15 of each 28-day cycle in doses ranging from 0.3 to 30 mg/kg. Blood samples were assessed serially for changes in lymphocyte subsets, PD-1^HIT cells and T cell effector function. IHC staining of paired biopsies for B7-H1, CD8, PD-1, CD4 and FoxP3 was performed to assess immunological status of the tumor at baseline and following treatment and then relative to peripheral readouts. Results: 42 patients (83% melanoma) were treated with varying doses of AMP-224 [0.3 mg/kg (n = 6); 1 mg/kg (n=4); 3 mg/kg (n = 4); 10 mg/kg (n = 22); 30 mg/kg (n = 6)]. Infusion reactions were common (69% across dose cohorts) and occurred mostly at higher doses (86% at the 10 mg/kg dose). No drug-related inflammatory adverse events were identified contrary to PD-1 blocking antibodies. Fresh pre-treatment biopsies were collected from 33/42 (78.5%) patients and paired biopsies have been collected thus far from 19/36 (52.7%) patients on study. 31% of baseline tumors were B7-H1+. Several PD readouts in the periphery showed reductions in PD-1^HIcells and emergence of a functional T cell response (increases in IFNg+, TNFa+, IL-2+ CD4 and CD8 T cells) in individual patients where partial response, stable disease, and mixed responses were seen. Conclusions: Data from peripheral readouts is consistent with hypothesized AMP-224 MoA. B7-H1+ was not always predictive of functional response to AMP-224 immunotherapy. Comprehensive PD readouts and evaluation of PK/PD relationships will be presented and may ultimately predict restoration of immune competence even in the presence of initial disease progression. Clinical trial information: NCT01352884.