First-in-human phase 1/2a study of T3011, an oncolytic HSV expressing IL-12 and PD-1 antibody, administered via intratumoral (IT) injection as monotherapy in advanced solid tumors, including recurrent or metastatic HNSCC

Oncolytic virus therapy represents a promising approach in cancer treatment due to its dual mechanisms of direct tumor lysis and immunomodulation. This study aims to evaluate the safety and efficacy of T3011, a novel oncolytic virus, administered intratumorally in patients with advanced solid tumors including head and neck squamous cell carcinoma (HNSCC). This study comprised three parts: Part I (single-dose escalation, 2.5 × 10 5 to 1 × 10 8 PFU/mL), Part II (multiple-dose escalation, 2.5 × 10 7 to 1 × 10 8 PFU/mL), and Part III (expansion phase at the recommended phase 2 dose (RP2D) of 1 × 10 8 PFU/mL). The primary endpoints for Parts I and II were safety and tolerability, with secondary endpoints including viral biodistribution, shedding, pharmacodynamics, and immunogenicity. In Part III, the primary endpoint was preliminary efficacy assessed according to RECIST v1.1 criteria, with safety as a key secondary endpoint. Exploratory endpoints for Parts II and III included pharmacodynamics and immune-related responses assessed by iRECIST criteria. Among the 87 patients treated with T3011 monotherapy in Part III, 74 were evaluable for efficacy. This group achieved an objective response rate (ORR) of 6.8% and a disease control rate (DCR) of 39.2%, with a median duration of response (DOR) of 10.6 months. Within the HNSCC cohort ( n = 28), 24 patients were evaluable, showing an ORR of 12.5% and a DCR of 33.3%. Notable immune modulation was observed with increased CD8 + T-cell infiltration and conversion of PD-L1-negative to PD-L1-positive tumor posttreatment. No dose-limiting toxicities (DLTs) or severe treatment-related adverse events (TRAEs) were reported. T3011 shows a favorable safety profile, immune-modulating effects, and preliminary efficacy in patients with advanced solid tumors. This study is registered with the China Drug Trial Registry (CTR20192464) and ClinicalTrials.gov (NCT05602792).