Background: A significant number of patients do not respond to PD-1/L1 blockade because there are no pre-existing tumor antigen-specific T-cells in their tumors ready to attack the cancer. We hypothesize that this lack of sufficient immune activation can be addressed by a combination therapy with an immune activating oncolytic virus such as T-VEC. Intralesional administration of T-VEC, a modified herpes simplex virus type-1, can selectively replicate in tumor tissue and stimulate a local and systemic antitumor immune response. Methods: This is a Phase 2 study of T-VEC plus pembro in patients with advanced melanoma whose disease progressed after prior therapy with a PD-1/L1 inhibitor. The primary endpoint is durable response rate. Secondary objectives include objective response rate in the injected, non-visceral non-injected and visceral lesions, progression free survival, overall survival and toxicity. Translational objectives include difference in T-cell infiltrate in responding vs non-responding tumors. Key eligibility criteria include unresectable melanoma; anti-PD-1/L1 based therapy must be the immediate previous line of treatment within 56 days prior to registration; no confirmed partial or complete response to prior anti-PD1 agents; Zubrod performance status 0-2; no active brain metastases; no history of autoimmune disease or toxicity requiring steroids; and adequate organ function. Subjects in cohort A must have at least one measurable visceral lesion; in cohort B subjects must not have visceral lesion. Subjects will receive intratumoral injection of T-VEC 1 million PFU/ml for cycle 1 followed by 100 million PFU/ml from cycle 2 to 36 (one cycle equals 21 days). Pembro 200mg IV will be given every 21 days. Tumor biopsy and research blood are taken at baseline and while on treatment at Day 28 (both injected and non-injected lesions). Tumor assessments are performed every 12 weeks, and treatment is continued while clinical benefit persists for up to 2 years. A total of 36 subjects will be enrolled in cohort A and 25 subjects in cohort B, with a Simon 2 stage design. Clinical trial information: NCT02965716