Initial results from a first in human trial incorporating accelerated dose titration of a novel immune stimulating oncolytic virus - VG161.
Authors: Zhao Ronghua , Cosman Rasha , Aggarwal Neha , O'Grady Aaron , Hsu Eugene , Ardolino Luke , Xia Huiqun , Chi Yiting , Qui Shi , Murad Yanal , Lee Erica , Jia William , Joshua Anthony M. 
Published: June 2021

e14574 Background: Oncolytic virus (OV) can specifically replicate in cancer cells causing cell lysis. Together with the expression of immune stimulating payloads, OV can induce an anti-tumor immune response. The aim of this study is to assess the safety, tolerability, and PK profile of VG161, a novel HSV-1 OV armed with IL12, IL15 with its receptor α unit, and PD-L1 antagonist (Fc-fused 14 amino acid peptide), after single intra-tumoral injection (IT) in patients with advanced refractory solid tumors. Methods: This is an open label, single-arm, accelerated titration design pilot trial. Based on preclinical NOAEL, the first cohort dose level was calculated as 5×107/subject, followed with 2 cohorts (1×108 and 2×108 PFU), 1-3 patients per cohort. One patient was treated in each cohort and the subsequent cohorts were initiated only after the safety observation of the current cohort was completed (21 days) with no DLT and no > 2 moderate toxicity events deemed possibly, probably, or definitely related to VG161, otherwise, it would be expanded per the 3+3 design. DNA copy number of VG161 was measured with qPCR in the tumor biopsy and blood, in urine for virus shedding, as well as swabs of injection site and mouth. Immune cytokines were measured with MSD assay (electrochemiluminescence detection) in blood. Peripheral lymphocyte subsets were analyzed with flowcytometry. Results: Three patients (1 per cohort) were treated and completed safety observation. No DLT, and 10 AEs (fever, low neutrophils and lymphocytes, etc.) were possibly, probably, or definitely related. Grade 3 fever was the only related SAE, which recovered in 3 days. Dose dependent increase of VG161 DNA copy was detected in the tumor 2-3 days after treatment (C-max: 10, 1000, and 1000000 times increase from low to high dose), in contrast, it remained undetectable in blood, oral swab, and urine. Virus DNA was detected in injection site swab for the patient at the highest dose level but not for those treated at lower dose levels. After dosing, increases of IL-12 (C-max: 2.0, 2.4, and 21 times of baseline), IL-15 (C-max: 1.6, 3.2, and 2.5 times of baseline), IFN-γ (C-max: 49, 638, and 236 times of baseline) and TNF-α (C-max: 2.3, 3.7, and 2.2 times of baseline) from low to high dose were seen. Peripheral lymphocyte subset analysis and immune profiling of injected tumor are ongoing. Interestingly, partial regression of multiple visible non-injected lesions was observed in 1 patient shortly after dosing, however no durable direct or abscopal responses were seen to date. Conclusions: Single IT injection of VG161 up to 2×108 PFU/subject is safe and well tolerated, with no unexpected viral spread or shedding. The post-dose increase in cytokines and the transit regression of non-injected lesions imply the activation of anti-cancer immunity induced by VG161. This holds potential for further dose optimization to assess the safety and efficacy. Clinical trial information: ACTRN12620000244909.