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Background Tumor-infiltrating lymphocyte (TIL) therapy was recently approved by the FDA for metastatic melanoma (MM), but its widespread implementation remains limited by significant toxicities associated with lymphodepleting chemotherapy and high-dose IL-2 regimens. Phase 1 trial TUNINTIL ( NCT04217473) evaluated a novel design where TILT-123 (igrelimogene litadenorepvec), an oncolytic adenovirus engineered to selectively replicate in cancer cells and produce tumor necrosis factor (TNF) and interleukin-2 (IL-2), replaces these toxic pre- and post-conditioning regimens.Methods Seventeen heavily pretreated (range of 1 to 7 prior cancer treatment lines) patients with immune checkpoint inhibitor (ICI)-refractory MM (8 cutaneous, 5 mucosal, 4 uveal) received TILT-123 intravenously and intratumorally in a dose-escalating manner across five cohorts. TILs were administered without preconditioning chemotherapy or post-infusion IL-2. Patients were evaluated for safety (primary endpoint), treatment response and survival outcomes. TILs phenotyping, neutralizing antibody titers in serum, immunohistochemistry of tumor biopsies, serum cytokine measurements, and viral shedding evaluation were performed to better understand the biological mechanisms of response.Results Treatment was well-tolerated with no dose-limiting toxicities. Most adverse events were mild to moderate, with fever (65%), fatigue (29%), and nausea (29%) being most common. PET imaging revealed 47% (7/15) disease control and 27% (4/15) complete and partial metabolic responses overall, and 40% responses on highest dose level. With RECIST1.1, the objective response rate was 11.7% (2/17) with disease control seen in 35% (6/17). Median overall survival was 447 days with 6 patients surviving more than 600 days. One mucosal melanoma patient is in complete response for more than 4 years.Viral DNA was detected in both injected and non-injected tumors, with increased T cell infiltration observed at both sites, suggesting effective systemic response. Patients with detectable virus in tumors demonstrated prolonged survival (p=0.0441). Interestingly, higher neutralizing antibody titers early in treatment correlated with improved disease control (p=0.0062). Moreover, decreased blood lymphocyte counts following TILT-123 administration (i.e. trafficking to tumors) was associated with better tumor control.Serum proteomic analysis revealed that patients with disease control exhibited a distinct inflammatory signature after initial viral treatment, suggesting that differential immune responses to TILT-123 may influence subsequent TIL therapy efficacy.Conclusions TILT-123 combined with TILs demonstrates good safety and promising efficacy in ICI-refractory melanoma, successfully eliminating toxic conditioning regimens while achieving durable responses, including in challenging non-cutaneous subtypes. This novel combination approach deserves continued clinical development as a potentially safer alternative to conventional TIL therapy. A phase 1b trial is ongoing ( NCT06961786).Trial Registration NCT04217473Ethics Approval The trial was approved by the Danish National Ethics Committee and the Danish Medicines Agency with the approval number 1905760. All approvals were obtained prior to inclusion of the first patient in the trial.Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.