Vectorized gene therapy of liver tumors: proof-of-concept of TG4023 (MVA-FCU1) in combination with flucytosine.
TG4023 is a modified vaccinia virus Ankara (MVA) containing the yeast-originated transgene FCU1, expressing cytosine deaminase and uracil phosphoribosyltransferase enzymes that transform the prodrug flucytosine (5-FC) into cytotoxic 5-fluorouracil (5-FU) and 5-fluorouridine-5′-monophosphate, respectively. This first-in-human study aimed to assess the maximum tolerated dose (MTD) of intratumoral (IT) TG4023 and the safety, feasibility, and proof-of-concept (PoC) of TG4023/5-FC combination to deliver high 5-FU concentrations in tumors.



Cancer patients without further therapeutic option and with at least one injectable primary or metastatic liver tumor underwent on day 1 a percutaneous IT injection of TG4023 at doses of 107, 108, or 4.108 plaque forming units (p.f.u.) using ultrasound imaging guidance, after a dose-limiting toxicities (DLTs)-driven 3 + 3 dose-escalating design. On day 2, patients were given intravenous and/or oral 5-FC at a dose of 200 mg/kg/day for 14 days and were followed for safety through day 43. Tumor response was assessed at week 6, according to RECIST. Plasma and tumor 5-FU concentrations were measured to establish the PoC.



In total, 16 patients completed treatment with TG4023 and 5-FC. One DLT/7 patients (ALT/aspartate aminotransferase transient increase) was observed at 4 × 108 p.f.u.; MTD was therefore not reached. The most frequent adverse events were pyrexia, asthenia, vomiting, and decreased appetite. Eight of 16 patients had stable disease. Mean 5-FU concentrations in plasma were 1.9 ± 2.6 ng/ml and 56 ± 30 ng/g in tumors. Seroconversion for anti-FCU1 antibodies was found for one patient from each cohort (16%, overall).



This phase I study demonstrated that IT injections of TG4023 were feasible and well tolerated; MTD was defined as 4 × 108 p.f.u. Therapeutic 5-FU concentrations in tumors established the virus-directed enzyme-prodrug therapy PoC.



NCT00978107.
Onco-Hematology and Immunology Department, Pasteur Hospital, Colmar.
F
F
Husseini
Clinical Research Unit, University Institute of Cancer, Oncopole, Toulouse.
J-P
JP
Delord
Medical Oncology Department, Lyon-Sud Hospital, Pierre-Bénite.
C
C
Fournel-Federico
Laboratory of Therapeutic Targeting in Oncology, Biology Center South, Lyon-Sud Hospital, Pierre-Bénite.
J
J
Guitton
Departments of Oncolytic Virus Research.
P
P
Erbs
Medical Affairs, Transgene SA, Illkirch-Graffenstaden.
M
M
Homerin
Medical Affairs, Transgene SA, Illkirch-Graffenstaden.
C
C
Halluard
Medical Affairs, Transgene SA, Illkirch-Graffenstaden.
C
C
Jemming
Medical Affairs, Transgene SA, Illkirch-Graffenstaden.
C
C
Orange
Medical Affairs, Transgene SA, Illkirch-Graffenstaden.
J-M
JM
Limacher
Hematology and Oncology Department, University Hospitals of Strasbourg, Hautepierre Hospital, Strasbourg, France.
J-E
JE
Kurtz
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003131:Combined Modality Therapy; D043525:Cytosine Deaminase / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005437:Flucytosine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005472:Fluorouracil / Q000097:blood / Q000493:pharmacokinetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics*; D006801:Humans; D015552:Injections, Intralesional; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D010430:Pentosyltransferases / Q000235:genetics* / Q000378:metabolism; D000075082:Proof of Concept Study; D019076:Transgenes; D014616:Vaccinia virus / Q000235:genetics
D005437:Flucytosine; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D043525:Cytosine Deaminase; D005472:Fluorouracil