Abstract LB179: Oncolytic virus TG6002 locates to tumors after intravenous infusion and induces tumor-specific expression of a functional pro-drug activating enzyme in patients with advanced gastrointestinal carcinomas
Authors: Bendjama Kaidre , Cassier Philippe , Moreno Victor , Doger Bernard , Calvo Emiliano , de Miguel Maria , Jungels Christiane , Erbs Philippe , Carpentier Damien , Sadoun Alain 
Published: July 2021

Abstract
Objective: TG6002 is a vaccinia virus deleted for Thymidine Kinase/Ribonucleotide Reductase and encoding the FCU1 enzyme that converts 5-Fluorocytosine (5-FC) to 5-Fluorouracil (5-FU). In a dose-escalation phase I study combining intravenous TG6002 and oral 5-FC in patients with advanced gastrointestinal carcinomas, exploratory analyses were performed to document TG6002 pharmacokinetic (PK) and biodistribution, and FCU1 function.
Methodology: A total of 10 patients, median age 60 years (range 50-69), received TG6002 infusions on days 1, 8 and 15 at the dose of 3x108 pfu (n=3) (low dose, LD) or 1x109 pfu (high dose, HD) (n=7) combined with 5-FC (4 times 50 mg/kg/day) on days 5 to 7, 12 to 14, and 19 to 28 for colorectal (n=6), esophagus (n=1), gastric (n=1), pancreatic (n=1) and ampulla of Vater (n=1) carcinomas. Blood was sampled 30 min, 3h and 24h after TG6002 infusion on day 1 and 15 for plasma TG6002 PK and one hour after intake of 5-FC at screening (single dose of 50 mg/kg) and on days 5, 7, 14 and 28 for serum 5-FC and 5-FU measurements. A metastasis biopsy was performed on day 5 along with synchronous blood sampling. Virus presence was assessed by qPCR and plaque assay, and 5-FC and 5-FU quantified using HPLC-MS. Neutralizing antibodies (NAb) titers were assessed using a plaque inhibition assay at baseline, days 28 and 43.
Results: TG6002 was detected by qPCR in plasma and was rapidly cleared with no patients showing trace of the virus beyond 3 hours after administration. On day 5, despite very scarce availability of biomaterial, the virus was detected in tumoral tissue in 1/3 and 2/7 patients of the LD and HD cohorts, respectively. 5-FC to 5-FU conversion was detected in tumor of all patients and the highest tumor concentrations of 5-FU (65 and 227 pg/mg of tissue, respectively) were found in 2 of the 3 patients in which virus was detected in the tumor. The other patients had tumor 5-FU concentrations ranging from 0.8 to 8.7 pg/mg. Those patients with highest tumor 5-FU levels had the highest level of serum 5-FU on day 5 (352 and 417 ng/mL, respectively). All other patients had levels of 5-FU ranging from 2 to 42 ng/mL, reflecting FCU1 activity. No 5-FU was detected after the intake of 5-FC during the screening period, excluding endogenous 5-FC to 5-FU conversion. Overall, blood 5-FU concentrations were 89±144, 50±96, 7±9 and 1±0.6 ng/ml on days 5, 7, 14 and 28, respectively, with no apparent differences between LD and HD cohorts. NAbs were developed by all patients on day 28 and could explain the decrease in blood 5-FU over the study course.
In conclusion, despite the sensitivity challenges associated with direct detection of viral particles in patient tumor tissue, our data suggest that TG6002 locates to tumors after intravenous administration, remains active and effectively express an active recombinant payload selectively in tumor tissue. The study is continuing with escalating doses of virus.
Citation Format: Kaidre Bendjama, Philippe Cassier, Victor Moreno, Bernard Doger, Emiliano Calvo, Maria de Miguel, Christiane Jungels, Philippe Erbs, Damien Carpentier, Alain Sadoun. Oncolytic virus TG6002 locates to tumors after intravenous infusion and induces tumor-specific expression of a functional pro-drug activating enzyme in patients with advanced gastrointestinal carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB179.