First-in-man Phase 1 Clinical Trial of Gene Therapy for Advanced Pancreatic Cancer: Safety, Biodistribution, and Preliminary Clinical Findings

Louis Buscail, Barbara Bournet, Fabienne Vernejoul, Gilles Cambois, Hubert Lulka, Naïma Hanoun, Marlène Dufresne, Aline Meulle, Alix Vignolle-Vidoni, Laetitia Ligat, Nathalie Saint-Laurent, Frédéric Pont, Sébastien Dejean, Marion Gayral, Frédéric Martins, Jérôme Torrisani, Odile Barbey, Fabian Gross, Rosine Guimbaud, Philippe Otal, Frédéric Lopez, Gérard Tiraby, Pierre Cordelier
Molecular Therapy. 2015-04-01; 23(4): 779-789
DOI: 10.1038/mt.2015.1

Buscail L(1), Bournet B(2), Vernejoul F(3), Cambois G(3), Lulka H(4), Hanoun
N(4), Dufresne M(4), Meulle A(4), Vignolle-Vidoni A(2), Ligat L(5),
Saint-Laurent N(5), Pont F(5), Dejean S(6), Gayral M(4), Martins F(7), Torrisani
J(4), Barbey O(8), Gross F(8), Guimbaud R(9), Otal P(10), Lopez F(5), Tiraby
G(3), Cordelier P(4).

Author information:
(1)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.
(2)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.
(3)Cayla InvivoGen Company, Research Department, Toulouse, France.
(4)1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2]
Inserm, UMR1037 CRCT, Toulouse, France.
(5)1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2]
Inserm, UMR1037 CRCT, Toulouse, France [3] Inserm, UMR1037 Proteomic Group-CRCT,
Toulouse, France.
(6)Department of Mathematics, Université Toulouse III-Paul Sabatier, Toulouse,
France.
(7)Inserm, UMR1048, Toulouse, France.
(8)CIC Biotherapies 511, CHU Toulouse and INSERM, Toulouse, France.
(9)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.
(10)1] Université Toulouse III-Paul Sabatier, UMR1037 CRCT, Toulouse, France [2]
Department of Radiology, CHU Toulouse-Rangueil, Toulouse, France.

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.