Background: Oncolytic virotherapy has emerged as a promising anticancer treatment. To date, almost all oncolytic viruses (OVs) are delivered via intratumoral (IT) injection, which limits its broad clinical application. Systemic delivery of OVs, a more practical option for patients (pts) without injectable lesions, allows both primary tumor and metastases treated simultaneously. However, due to concerns for immune clearance and the potential cytokine storms, very few studies thus far are conducted using OVs intravenously. T3011 is a genetically modified, next-generation oncolytic HSV-1 expressing IL-12 and PD-1 antibody. Extensive preclinical studies have demonstrated the feasibility, safety and efficacy of T3011 delivered intravenously. Here, we present preliminary results of IV T3011 as a single agent. Methods: In this phase 1/2a, multi-center, open label, dose escalation and expansion study, T3011 was administered intravenously on Days 1, 4, 8 of a 21-day cycle in pts with advanced solid tumors. The primary objective was to evaluate the safety and tolerability of escalating doses of IV T3011, characterize dose limiting toxicities (DLTs) and identify the MTD and RP2D of IV T3011. Phase 1 portion used a 3+3 design in 4 escalating cohorts (1×10⁶, 1×10⁷, 1×10⁸, 3×10⁸ PFU). Pharmacokinetics, immunogenicities and pharmacodynamic profiles were studied in various samples. Results: As of Jan 2023, 10 pts received IV T3011 therapy: 4 in Cohort 1, 3 in Cohort 2, and 3 in Cohort 3. Median number of doses was 8. T3011 was well tolerated with no ≥ Grade 3 treatment-related adverse events (TRAEs) and no DLTs to date. Nausea and infusion-related reaction (including postdose delayed fever, chills, rigors, etc.) were the most common TRAEs. 7 of 10 pts had ≥ 1 tumor assessment, 4 achieved stable disease (SD) by RECIST 1.1 with a disease control rate of 57.1%, 2 had SD for ≥ 6 months. 1 pt had a postdose tumor biopsy revealing T cell activation via transcriptome profiling and gene ontology analysis. T3011 DNA was detected in blood in 9/10 pts at 0.5 hours after the 1^st dose and its level was dose-dependent and increased with repeated doses. T3011 DNA clearance was observed at 4-7 days after dosing. Saliva and urine samples from all pts were tested for T3011 DNA, only one was positive with very low DNA copies in a saliva sample at 0.5 h after the 2^nd dose from a pt in Cohort 1. Of note, pre-existing HSV-1 IgG had no impact on T3011 activity. Conclusions: IV T3011 monotherapy was well tolerated and safe at the first 3 dose levels, highly unlikely to be transmissible. Preliminary efficacy was encouraging. Our results also suggest T3011 IV treatment could stimulate anti-tumor immunity in the tumor microenvironment. Clinical trial information: NCT04780217.