Background: VG2025 is a non-attenuated HSV-1 Oncolytic virus (OV). The wildtype neurovirulence is controlled by the Transcription and Translation Dual Regulation (TTDR) of ICP27 and ICP34.5 proteins. IL-12, IL-15, IL-15Ra payloads are controlled by tumor promoter CxCR4. The native promoter of ICP27 was replaced with a promoter for Carcinoembryonic Antigen (CEA). Here we report a first-in-human, open label, study to evaluate the safety, pharmacokinetics (PK), and biologic effects of VG2025 in patients (pts) with advanced solid tumors progressed after standard of care from China and United States. The study is actively recruiting. NCT05266612. Methods: Dose escalation follows a 3+3 design at 4 dose levels as intratumoral, and image guided injections into deep lesions on days 1 and 15 of each 28 days treatment cycle. PK and viral shedding (DNA), samples from biopsies, blood, urine, and swabs from injection site and other anatomical locations were analyzed by PCR. Changes of cytokines and lymphocyte subsets in blood were also observed as pharmacodynamic parameters. Results: As of 10 Jan 2023, 10 pts received doses of 1.0x10^8 and 2.0x10^8 PFU. 5 males and 5 females with the median age of 58 years were enrolled. 20% were PD(L)1 refractory, 20% had 2 Prior lines of therapy and 60% ≥3. The Median CEA level was 7.4. Tumor types were: 2 Duodenal Adeno Ca., 1 Pancreatic, 1 Ovarian, 1 Leiomyosarcoma, 1 Salivary Duct Ca., 1 Hepatocellular Ca (HCC), 1 Intrahepatic Cholangiocarcinoma (ICC), 1 Colorectal Ca (CRC) and 1 Colon Ca. No Dose Limiting Toxicities were observed. Any grade treatment-related AEs (TRAEs) was 70%, the most common TRAEs was fever 60%. Grade ≥3 TRAEs were 50% [3 pts had grade 4 Lymphocyte decreased (all recovered)], 1 had grade 3 COVID-19 and 1 had grade 3 nausea and vomiting. 4 pt had SAEs (2 cases of COVID-19, 1 Ascites and 1 Nausea and Vomiting). No TRAEs leading to dose reduction and treatment discontinuation. No pts had positive viral shedding. 4 pts were efficacy evaluable; ORR 25% (1 pt with ICC had confirmed PR with -45%) and DCR 100% based on RECIST v1.1. The PR pt had meaningful reductions in CEA levels. Tumor shrinkage was also observed in non-injected lesions demonstrating an abscopal effect. Nanostring analysis of paired biopsies from the PR pt demonstrate upregulation of genes for integrin signaling pathway, activation of CD8+ T cells and T cell-based immunity, upregulation of antigen-presenting MHC (HLA-DQA1 and HLA-DRB1) and chemokine receptor (CMKLR1) genes. Cellular immunity was activated by upregulation of Th1 cells, macrophage-associated genes and downregulation of Treg-associated genes. The results are consistent with the mechanism of action of VG2025. Analysis is ongoing with other subjects. Conclusions: Monotherapy activity was observed with an acceptable safety profile in heavily pretreated pts with advanced solid tumors. Clinical trial information: NCT05266612.