Phase I clinical trial of a genetically modified and oncolytic vaccinia virus GL-ONC1 with green fluorescent protein imaging.

Abstract

2530 Background: GL-ONC1 is a genetically engineered vaccinia virus attenuated by insertion of the RUC-GFP (Renilla luciferase and Aequorea green fluorescent protein fusion gene), beta-galactosidase (lacZ) and beta-glucuronidase (gusA) reporter genes into the F14.5L, J2R (thymidine kinase) and A56R (hemaglutinin) loci. A phase I clinical trial of iv GL-ONC1 was pursued to evaluate safety, tolerability, tumour delivery, neutralizing antibody development and anti-tumour activity. Methods: GL-ONC1 was administered to patients with advanced solid tumours at escalating doses (1×105, 1×106, 1×107, 1×108, 1×109, 3×109 plaque-forming units (pfu) on day 1; 1.667×107 and 1.667×108 pfu on day 1-3 of a 28-day cycle) using a 3+3 dose escalation design. Green fluorescent protein (GFP) imaging was performed on skin rash and mucosal tumour lesions at baseline and after each cycle. Optional tumour biopsies were obtained for pharmacodynamic and viral delivery evaluation. Results: 27 patients (21 males, median age 60 years) were treated. One of six patients at the 1x109 pfu dose level developed a dose-limiting, grade 3 rise in aspartate transaminase levels after a single infusion. Other reported adverse events (grade 1/2) included pyrexia (21), musculoskeletal pain (9), fatigue (8), nausea (7), and vomiting (4). Two patients developed skin rash during the first week of treatment, which appeared green by GFP and were positive to viral plaque assay (VPA). VPA of blood, urine, stool and sputum were negative for viral shedding in all but one patient who had positive shedding for 11 days. Increased neutralizing antibody titres were detected in all tested patients apart from one. Best response by RECIST was stable disease at 48 weeks (1), 24 weeks (3) and 8-12 weeks (5). A patient with squamous cell carcinoma of the tongue had a biopsy after 4 cycles which showed positive IHC staining of vaccinia virus. This is the first time that a virus is shown to be delivered to solid tumour after iv delivery. Conclusions: GL-ONC1 administered iv is well tolerated, with documented colonisation in patient tumour, and preliminary evidence of anti-tumour activity.