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Mol Ther. 2015 Apr;23(4):779-89. doi: 10.1038/mt.2015.1. Epub 2015 Jan 14.

First-in-man phase 1 clinical trial of gene therapy for advanced pancreatic cancer: safety, biodistribution, and preliminary clinical findings.

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.

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.

PMID:
25586689
PMCID:
PMC4395782
DOI:
10.1038/mt.2015.1
[Indexed for MEDLINE]
Free PMC Article

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