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

被引：89

作者：

Buscail, Louis ^{[1
,2
,3
,4
,5
]}

Bournet, Barbara ^{[1
,2
,3
]}

Vernejoul, Fabienne ^{[6
]}

Cambois, Gilles ^{[6
]}

Lulka, Hubert ^{[2
,3
]}

Hanoun, Naima ^{[2
,3
]}

Dufresne, Marlene ^{[2
,3
]}

Meulle, Aline ^{[2
,3
]}

Vignolle-Vidoni, Alix ^{[1
,2
,3
]}

Ligat, Laetitia ^{[2
,3
,7
]}

Saint-Laurent, Nathalie ^{[2
,3
,7
]}

Pont, Frederic ^{[2
,3
,7
]}

Dejean, Sebastien ^{[8
]}

Gayral, Marion ^{[2
,3
]}

Martins, Frederic ^{[9
]}

Torrisani, Jerome ^{[2
,3
]}

Barbey, Odile ^{[4
,5
]}

Gross, Fabian ^{[4
,5
]}

Guimbaud, Rosine ^{[2
,3
,10
]}

Otal, Philippe ^{[2
,11
]}

Lopez, Frederic ^{[2
,3
,7
]}

Tiraby, Gerard ^{[6
]}

Cordelier, Pierre ^{[2
,3
]}

机构：

[1] CHU Toulouse Rangueil, Dept Gastroenterol, Toulouse, France

[2] Univ Toulouse 3, CRCT, UMR1037, F-31037 Toulouse 1, France

[3] CRCT, INSERM, UMR1037, Toulouse, France

[4] CHU Toulouse, CIC Biotherapies 511, Toulouse, France

[5] Fac Med Toulouse, INSERM, F-31073 Toulouse, France

[6] Cayla InvivoGen Co, Res Dept, Toulouse, France

[7] CRCT, UMR1037, INSERM, Prote Grp, Toulouse, France

[8] Univ Toulouse 3, Dept Math, F-31037 Toulouse 1, France

[9] Fac Med Toulouse, INSERM, UMR1048, F-31073 Toulouse, France

[10] CHU Toulouse Rangueil, Dept Oncol, Toulouse, France

[11] CHU Toulouse Rangueil, Dept Radiol, Toulouse, France

来源：

MOLECULAR THERAPY | 2015年 / 23卷 / 04期

关键词：

SOMATOSTATIN RECEPTOR SST2; GEMCITABINE; EXPRESSION; RADIOTHERAPY; INHIBITION; CARCINOMA; SURVIVAL; CELLS;

D O I：

10.1038/mt.2015.1

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：779 / 789

页数：11

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