Background VG161 is a non-attenuated HSV-1 Oncolytic virus (OV) with IL-12, IL-15, IL-15Ra and PD-L1 blocking payloads. Here we report an open label, study to evaluate the safety, pharmacokinetics (PK), and biologic effects of VG161 in patients (pts) with advanced pancreatic cancer progressed after standard of care. The study is actively recruiting. NCT05162118.

Methods Dose escalation follows a 3+3 design at 3 dose levels as VG161 intratumoral injections on days 1,2,3 and Nivolumab treatment on days 22 and 28 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. Samples were harvested on C1D1, C1D7 and C2D1 which were analyzed by single-cell sequencing.

Results As of 31 May 2023, 13 pts received doses of 1.5x10⁸ PFU, 2.0x10⁸ PFU and 3.0x10⁸ PFU. 10 males and 3 females with the median age of 58 years were enrolled. 76.9% were PD(L)1 refractory,46.2% had 2 Prior lines of therapy and 13% ≥3. No Dose Limiting Toxicities were observed. Any grade treatment-related AEs (TRAEs) was 5.7%. The most common TRAEs were all grade 1 and 2. 9 pts had SAEs, including 1 pts (7%) with a related SAE (cytokine release syndrome). No TRAEs leading to dose reduction and treatment discontinuation. No pts had positive viral shedding. 11 pts were efficacy evaluable; ORR 9.1% and DCR 23.1% based on RECIST v1.1. Tumor shrinkage was also observed in non-injected lesions demonstrating an abscopal effect. According to the results of single cell data analysis, patients with advanced pancreatic cancer treated with VG161 remodeled the tumor microenvironment in the tumor, torqued from a cold tumor to a hot tumor, reduced the number of tumor cells, and significantly increased T and NK cell infiltration (T cells increased by 15% in injected lesions and NK cells increased by 3% in non-injected lesions after VG161 dosing). Moreover, patients were also more sensitive to subsequent immunosuppressive therapy.

Conclusions VG161 can significantly improve the immune microenvironment and provide favorable conditions for the combination of nivolumab.

Trial Registration NCT05162118

Ethics Approval Approval Letter of Clinical Research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University. ID:IIT20210108C