title: First-in-man phase 1 clinical trial of gene therapy for advanced pancreatic cancer: safety, biodistribution, and preliminary clinical findings.
abstract: This phase 1 trial was aimed to determine the safety, pharmacokinetics, and preliminary clinical activity of CYL-02, a nonviral gene therapy product that sensitizes pancreatic cancer cells to chemotherapy. CYL-02 was administrated using endoscopic ultrasound in 22 patients with pancreatic cancer that concomitantly received chemotherapy (gemcitabine). The maximum-tolerated dose (MTD) exceeded the maximal feasible dose of CYL-02 and was not identified. Treatment-related toxicities were mild, without serious adverse events. Pharmacokinetic analysis revealed a dose-dependent increase in CYL-02 DNA exposure in blood and tumors, while therapeutic RNAs were detected in tumors. No objective response was observed, but nine patients showed stable disease up to 6 months following treatment and two of these patients experienced long-term survival. Panels of plasmatic microRNAs and proteins were identified as predictive of gene therapy efficacy. We demonstrate that CYL-02 nonviral gene therapy has a favorable safety profile and is well tolerated in patients. We characterize CYL-02 biodistribution and demonstrate therapeutic gene expression in tumors. Treated patients experienced stability of disease and predictive biomarkers of response to treatment were identified. These promising results warrant further evaluation in phase 2 clinical trial.
authors.affiliation: 1] Department of Gastroenterology, CHU Toulouse - Rangueil, Toulouse, France [2] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [3] Inserm, UMR1037 CRCT, Toulouse, France [4] CIC Biotherapies 511, CHU Toulouse and INSERM, Toulouse, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Buscail
authors.affiliation: 1] Department of Gastroenterology, CHU Toulouse - Rangueil, Toulouse, France [2] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [3] Inserm, UMR1037 CRCT, Toulouse, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bournet
authors.affiliation: Cayla InvivoGen Company, Research Department, Toulouse, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Vernejoul
authors.affiliation: Cayla InvivoGen Company, Research Department, Toulouse, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Cambois
authors.affiliation: 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Lulka
authors.affiliation: 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France.
authors.forename: Naïma
authors.initials: N
authors.lastname: Hanoun
authors.affiliation: 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Dufresne
authors.affiliation: 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Meulle
authors.affiliation: 1] Department of Gastroenterology, CHU Toulouse - Rangueil, Toulouse, France [2] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [3] Inserm, UMR1037 CRCT, Toulouse, France.
authors.forename: Alix
authors.initials: A
authors.lastname: Vignolle-Vidoni
authors.affiliation: 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France [3] Inserm, UMR1037 Proteomic Group-CRCT, Toulouse, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Ligat
authors.affiliation: 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France [3] Inserm, UMR1037 Proteomic Group-CRCT, Toulouse, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Saint-Laurent
authors.affiliation: 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France [3] Inserm, UMR1037 Proteomic Group-CRCT, Toulouse, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Pont
authors.affiliation: Department of Mathematics, Université Toulouse III-Paul Sabatier, Toulouse, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Dejean
authors.affiliation: 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Gayral
authors.affiliation: Inserm, UMR1048, Toulouse, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Martins
authors.affiliation: 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Torrisani
authors.affiliation: CIC Biotherapies 511, CHU Toulouse and INSERM, Toulouse, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Barbey
authors.affiliation: CIC Biotherapies 511, CHU Toulouse and INSERM, Toulouse, France.
authors.forename: Fabian
authors.initials: F
authors.lastname: Gross
authors.affiliation: 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France [3] Department of Oncology, CHU Toulouse-Rangueil, Toulouse, France.
authors.forename: Rosine
authors.initials: R
authors.lastname: Guimbaud
authors.affiliation: 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Department of Radiology, CHU Toulouse-Rangueil, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Otal
authors.affiliation: 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France [3] Inserm, UMR1037 Proteomic Group-CRCT, Toulouse, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lopez
authors.affiliation: Cayla InvivoGen Company, Research Department, Toulouse, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Tiraby
authors.affiliation: 1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2] Inserm, UMR1037 CRCT, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cordelier
mesh_terms: D000368:Aged; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000628:therapy*; D014018:Tissue Distribution