Background: HF10, a bioselected replication-competent oncolytic virus derived from HSV-1, has been evaluated in combination with ipilimumab (ipi) in a Phase II trial (NCT02272855) in unresectable/unresected Stage IIIB-IV melanoma pts. Herein we report the recent efficacy and gene expression findings correlating with responders. Methods: HF10 injected into single or multiple tumors (1 x 10⁷ TCID₅₀/mL/dose, up to 5mL depending on tumor size and numbers); 4 injections q1wk; then up to 15 injections q3wk. Four ipi IV infusions (3 mg/kg; concurrent with HF10) were administered q3wk. AEs assessed per CTCAE 4.0. Tumor responses were assessed per mWHO and irRC at 12, 18, 24, 36 and 48 wks for patients (pts) continuing on HF10 monotherapy. Primary endpoint was Best Overall Response Rate (BORR) at 24 wks. Evaluation of correlative studies (nCounter PanCancer Immune Profiling Panel) including tumor biopsy was performed at baseline and on Days 85 and 169. Results: 46 pts were enrolled and treated: 59% men, median age 67 yrs (range 28 to 91); disease stage 20% IIIB, 43% IIIC and 37% IV; 57% were treatment naïve and 43% with ≥ 1 prior cancer therapy for unresectable/metastatic melanoma. HF10+ipi combination was well tolerated. HF10 adverse event (AE) profile was similar in combination with ipi as in HF10 monotherapy. 28.3% pts had treatment-related ≥G3 AEs, and the majority of ≥G3 AEs were due to ipi. Of the 44 efficacy evaluable pts, irRC BORR at 24 weeks was 41% (18% irCR and 23% irPR); disease stability rate was 68% (27% irSD). As of Feb 07, 2018, median PFS was 19 months and median overall survival was 26 months. Responding tumors exhibited an activation of the adaptive immune response with increased total tumor infiltrating lymphocytes and CD8+ T-cells, and decreased CD4+ T-cells. Conclusions: The combination HF10 and ipilimumab treatment demonstrated a favorable benefit/risk profile and encouraging antitumor activity in advanced melanoma pts by inducing immune-cell infiltration in the tumor microenvironment. Clinical trial information: NCT02272855