Abstract 3532A: Development of gene therapy for pancreatic carcinoma: from experimental models to phase I clinical trial.

Abstract

Abstract Background: the median survival of patients diagnosed with locally advanced or metastatic pancreatic adenocarcinoma (PDA) is 4 to 6 months. Chemotherapies (gemcitabine, FOLFIRINOX) and molecular targeted therapies only offer a marginal survival benefit. Consequently, we developed new strategies based on therapeutic gene transfer to help alleviate the dismal prognosis of PDA. We demonstrated that transferring SSTR2 gene in PDA experimental models strongly inhibited tumor progression. We generated DCK::UMK fusion gene to chemosensitize tumor cells to gemcitabine to provoke tumor shrinkage in immune competent animals. Based on these promising results, we asked whether combining SSTR2 and DCK::UMK genes delivered by a non-viral vector may impede PDA growth in patients. Methods: in this first-in-man clinical trial, 22 patients (12 first line, 10 second line) were included in the CHU of Toulouse from 12/2010 to 9/2012. Four different doses (125, 250, 500 and 1000μg) of the gene therapy product (GTP) were injected twice using endoscopic ultrasound (EUS) (day 1 and day 28). Patients concomitantly received gemcitabine for 2 months. Results: the feasibility of this approach is excellent, as all the patients were successfully injected despite differences in the site and the size of the primary tumor, and pre-existing treatments (biliary stent, surgical bypass). No serious adverse events related to the GTP were recorded. We found that less than 0.001% of GTP was detected in blood, while urine was negative in all cases. We found that CA 19.19 levels decreased in 68% (15/22) of patients following gene therapy. In first line patients, we demonstrated partial tumor shrinkage in 2 cases (16%), stable disease in 9 cases (75%), and tumor progression in 1 case (8%). In these latter patients, progression-free survival and median survival following gene therapy reached 7 and 11.3 months, respectively. Conclusions: all together, we demonstrated for the first time that delivering antitumoral genes using non-viral vectors by EUS is feasible and safe in patients with advanced PDA. As our preliminary results tend to demonstrate therapeutic efficacy, we are currently designing a phase II trial based on this approach. Citation Format: Louis Buscail, Barbara Bournet, Fabienne Vernejoul, Hubert Lulka, Gilles Cambois, Naima Hanoun, Fabian Gross, Jean Tiraby, Pierre Cordelier. Development of gene therapy for pancreatic carcinoma: from experimental models to phase I clinical trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3532A. doi:10.1158/1538-7445.AM2013-3532A