To date, pancreatic adenocarcinoma (PDAC) can’t be diagnosed early. Consequently, a majority of p... more To date, pancreatic adenocarcinoma (PDAC) can’t be diagnosed early. Consequently, a majority of patient (80%) display an advanced disease that results in a low resection rate leading to a dismal overall median survival of less than 6 months. We extensively demonstrated that delivering SSTR2, DCK and UMK genes using non-viral vectors strongly inhibit tumor progression and dissemination in relevant experimental models of PDAC. Consequently, we designed a GMP-grade gene therapy product, namely CYL-02, encoding for the above mentioned therapeutic proteins, delivered by a non-viral vector for the management of 24 patients diagnosed with advanced PDAC. In this phase I clinical trial, gene therapy was administered in dose-escalation in the tumors using endoscopic ultrasound. Patients received gemcitabine during this protocol. We demonstrate that the intratumoral injection of the gene therapy product is feasible, well tolerated and safe, and results in the presence and the expression of CYL-02 in the tumors. Consequently, tumor progression is inhibited during the course of the protocol. In patients with locally advanced PDAC at the time of diagnosis, tumor size and serum levels of CA 19-9 significantly decreased following gene therapy regardless of the previous lines of treatment and median progression free survival and median overall survival reaches 6.4 and 11.4 months respectively. In addition, we carried out several advanced proteomic and circulating miRNAs analyses to identify diagnostic biomarkers predictive and/or indicative of treatment response and follow-up, to select clinical trial participants and/or to tailor therapy for individual patient. We already identified several biomarkers of clinical interest using either CE-MS (capillary electrophoresis coupled with mass spectrometry) or high throughput q(RT)PCR for peptide and miRNA identification, respectively, to create a clear prescription path for gene therapy in forthcoming clinical trials. Based on these preliminary yet very encouraging results, we propose that patients may clinically benefit from this approach. Accordingly, we are now entering phase II clinical trial using CYL-02 gene therapy product in patients diagnosed with locally advanced PDAC. Citation Format: Louis Buscail, Barbara Bournet, Fabienne Vernejoul, Gilles Cambois, Hubert Lulka, Naima Hanoun, Aline Meulle, Alix Vignolle-Vidoni, Odile Barbey, Fabian Gross, Rosine Guimbaud, Philippe Ottal, Gerard Tiraby, Pierre Cordelier. Non-viral gene therapy for pancreatic cancer, from preclinical models to phase II clinical trial. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B96.
Pancreatic cancer is a public health problem because of its increasing incidence, the absence of ... more Pancreatic cancer is a public health problem because of its increasing incidence, the absence of early diagnostic tools, and its aggressiveness. Despite recent progress in chemotherapy, the 5-year survival rate remains below 5%. Liquid biopsies are of particular interest from a clinical point of view because they are non-invasive biomarkers released by primary tumours and metastases, remotely reflecting disease burden. Pilot studies have been conducted in pancreatic cancer patients evaluating the detection of circulating tumour cells, cell-free circulating tumour DNA, exosomes, and tumour-educated platelets. There is heterogeneity between the methods used to isolate circulating tumour elements as well as the targets used for their identification. Performances for the diagnosis of pancreatic cancer vary depending of the technique but also the stage of the disease: 30–50% of resectable tumours are positive and 50–100% are positive in locally advanced and/or metastatic cases. A signifi...
Coronary artery disease (CAD) is the most prevalent cause of mortality and morbidity worldwide an... more Coronary artery disease (CAD) is the most prevalent cause of mortality and morbidity worldwide and the number of individuals at risk is increasing. To better manage cardiovascular diseases, improved tools for risk prediction including the identification of novel accurate biomarkers are needed. MicroRNA (miRNA) are essential post-transcriptional modulators of gene expression leading to mRNA suppression or translational repression. Specific expression profiles of circulating miRNA have emerged as potential noninvasive diagnostic biomarkers of diseases. The aim of this study was to identify the potential diagnostic value of circulating miRNA with CAD. Circulating miR-145, miR-155, miR-92a and let-7c were selected and validated by quantitative PCR in 69 patients with CAD and 30 control subjects from the cross-sectional study GENES. The expression of miR-145, miR-155 and let-7c showed significantly reduced expression in patients with CAD compared to controls. Multivariate logistic regres...
International journal of molecular sciences, Jan 8, 2017
A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of deat... more A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral), molecular tools (interference RNA, genome editing) and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes). The latest developments in pancreatic carcinoma gene therapy are described including gene-based tumor cell sensitization to chemotherapy, vaccination and adoptive immunotherapy (chimeric antigen receptor T-cells st...
Widespread application of gene therapy will depend on the development of simple methods to regula... more Widespread application of gene therapy will depend on the development of simple methods to regulate the expression of therapeutic genes. Here we harness an endogenous signaling pathway to regulate therapeutic gene expression through diet. The GCN2-eIF2α signaling pathway is specifically activated by deficiencies in any essential amino acid (EAA); EAA deficiency leads to rapid expression of genes regulated by ATF4-binding cis elements. We found that therapeutic genes under the control of optimized amino acid response elements (AAREs) had low basal expression and high induced expression. We applied our system to regulate the expression of TNFSF10 (TRAIL) in the context of glioma therapy and found that intermittent activation of this gene by EEA-deficient meals retained its therapeutic efficacy while abrogating its toxic effects on normal tissue. The GCN2-eIF2α pathway is expressed in many tissues, including the brain, and is highly specific to EAA deficiency. Our system may be particularly well suited for intermittent regulation of therapeutic transgenes over short or long time periods.
Journal of Hematotherapy Amp Stem Cell Research, Nov 1, 2002
Several lines of evidence suggest a potential major role for interferon (IFN) in controlling HIV-... more Several lines of evidence suggest a potential major role for interferon (IFN) in controlling HIV-1 replication. However, this inhibition is moderate and is reversible upon IFN removal. To achieve prolonged high concentrations of IFN at the site of infection, we devised an SV40-based vector, SV[HIVLTR]IFN, to direct the synthesis of human IFN-alpha2, by employing a virus-trans-activated human IFN-alpha2 gene to be transcribed in response to HIV-1 infection. Expression of IFN-alpha2 was confirmed by Northern and Western blotting, in SV[HIVLTR]IFN-transduced, HIV-1-challenged human lymphocyte lines and primary human lymphocytes. SV[HIVLTR]IFN-transduced cells showed no evidence of HIV-1-related cytophatic effects when challenged with high doses of HIV-1(NL4-3). As measured by supernatant HIV-1 p24 antigen concentration, IFN-alpha2-expressing cell lines and peripheral blood lymphocytes (PBL) were protected from high-dose challenges of HIV-1. rSV40-delivered IFN-alpha2 inhibited gp120 protein synthesis and expression of HIV-1 mRNAs. Finally, Southern analysis revealed that levels of proviral DNA were markedly reduced in SV[HIVLTR]IFN-transduced cells compared to control cultures. IFN-alpha2 expression driven by HIVLTR delivered by an rSV40 vector thus strongly inhibits HIV-1 replication, probably by blocking a preintegration step in HIV-1 infection. Targeted expression of IFN-alpha2 delivered by SV40 can thus repress HIV-1 replication, and may be a useful approach to HIV-1 treatment.
To date, pancreatic adenocarcinoma (PDAC) can’t be diagnosed early. Consequently, a majority of p... more To date, pancreatic adenocarcinoma (PDAC) can’t be diagnosed early. Consequently, a majority of patient (80%) display an advanced disease that results in a low resection rate leading to a dismal overall median survival of less than 6 months. We extensively demonstrated that delivering SSTR2, DCK and UMK genes using non-viral vectors strongly inhibit tumor progression and dissemination in relevant experimental models of PDAC. Consequently, we designed a GMP-grade gene therapy product, namely CYL-02, encoding for the above mentioned therapeutic proteins, delivered by a non-viral vector for the management of 24 patients diagnosed with advanced PDAC. In this phase I clinical trial, gene therapy was administered in dose-escalation in the tumors using endoscopic ultrasound. Patients received gemcitabine during this protocol. We demonstrate that the intratumoral injection of the gene therapy product is feasible, well tolerated and safe, and results in the presence and the expression of CYL-02 in the tumors. Consequently, tumor progression is inhibited during the course of the protocol. In patients with locally advanced PDAC at the time of diagnosis, tumor size and serum levels of CA 19-9 significantly decreased following gene therapy regardless of the previous lines of treatment and median progression free survival and median overall survival reaches 6.4 and 11.4 months respectively. In addition, we carried out several advanced proteomic and circulating miRNAs analyses to identify diagnostic biomarkers predictive and/or indicative of treatment response and follow-up, to select clinical trial participants and/or to tailor therapy for individual patient. We already identified several biomarkers of clinical interest using either CE-MS (capillary electrophoresis coupled with mass spectrometry) or high throughput q(RT)PCR for peptide and miRNA identification, respectively, to create a clear prescription path for gene therapy in forthcoming clinical trials. Based on these preliminary yet very encouraging results, we propose that patients may clinically benefit from this approach. Accordingly, we are now entering phase II clinical trial using CYL-02 gene therapy product in patients diagnosed with locally advanced PDAC. Citation Format: Louis Buscail, Barbara Bournet, Fabienne Vernejoul, Gilles Cambois, Hubert Lulka, Naima Hanoun, Aline Meulle, Alix Vignolle-Vidoni, Odile Barbey, Fabian Gross, Rosine Guimbaud, Philippe Ottal, Gerard Tiraby, Pierre Cordelier. Non-viral gene therapy for pancreatic cancer, from preclinical models to phase II clinical trial. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B96.
Pancreatic cancer is a public health problem because of its increasing incidence, the absence of ... more Pancreatic cancer is a public health problem because of its increasing incidence, the absence of early diagnostic tools, and its aggressiveness. Despite recent progress in chemotherapy, the 5-year survival rate remains below 5%. Liquid biopsies are of particular interest from a clinical point of view because they are non-invasive biomarkers released by primary tumours and metastases, remotely reflecting disease burden. Pilot studies have been conducted in pancreatic cancer patients evaluating the detection of circulating tumour cells, cell-free circulating tumour DNA, exosomes, and tumour-educated platelets. There is heterogeneity between the methods used to isolate circulating tumour elements as well as the targets used for their identification. Performances for the diagnosis of pancreatic cancer vary depending of the technique but also the stage of the disease: 30–50% of resectable tumours are positive and 50–100% are positive in locally advanced and/or metastatic cases. A signifi...
Coronary artery disease (CAD) is the most prevalent cause of mortality and morbidity worldwide an... more Coronary artery disease (CAD) is the most prevalent cause of mortality and morbidity worldwide and the number of individuals at risk is increasing. To better manage cardiovascular diseases, improved tools for risk prediction including the identification of novel accurate biomarkers are needed. MicroRNA (miRNA) are essential post-transcriptional modulators of gene expression leading to mRNA suppression or translational repression. Specific expression profiles of circulating miRNA have emerged as potential noninvasive diagnostic biomarkers of diseases. The aim of this study was to identify the potential diagnostic value of circulating miRNA with CAD. Circulating miR-145, miR-155, miR-92a and let-7c were selected and validated by quantitative PCR in 69 patients with CAD and 30 control subjects from the cross-sectional study GENES. The expression of miR-145, miR-155 and let-7c showed significantly reduced expression in patients with CAD compared to controls. Multivariate logistic regres...
International journal of molecular sciences, Jan 8, 2017
A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of deat... more A recent death projection has placed pancreatic ductal adenocarcinoma as the second cause of death by cancer in 2030. The prognosis for pancreatic cancer is very poor and there is a great need for new treatments that can change this poor outcome. Developments of therapeutic innovations in combination with conventional chemotherapy are needed urgently. Among innovative treatments the gene therapy offers a promising avenue. The present review gives an overview of the general strategy of gene therapy as well as the limitations and stakes of the different experimental in vivo models, expression vectors (synthetic and viral), molecular tools (interference RNA, genome editing) and therapeutic genes (tumor suppressor genes, antiangiogenic and pro-apoptotic genes, suicide genes). The latest developments in pancreatic carcinoma gene therapy are described including gene-based tumor cell sensitization to chemotherapy, vaccination and adoptive immunotherapy (chimeric antigen receptor T-cells st...
Widespread application of gene therapy will depend on the development of simple methods to regula... more Widespread application of gene therapy will depend on the development of simple methods to regulate the expression of therapeutic genes. Here we harness an endogenous signaling pathway to regulate therapeutic gene expression through diet. The GCN2-eIF2α signaling pathway is specifically activated by deficiencies in any essential amino acid (EAA); EAA deficiency leads to rapid expression of genes regulated by ATF4-binding cis elements. We found that therapeutic genes under the control of optimized amino acid response elements (AAREs) had low basal expression and high induced expression. We applied our system to regulate the expression of TNFSF10 (TRAIL) in the context of glioma therapy and found that intermittent activation of this gene by EEA-deficient meals retained its therapeutic efficacy while abrogating its toxic effects on normal tissue. The GCN2-eIF2α pathway is expressed in many tissues, including the brain, and is highly specific to EAA deficiency. Our system may be particularly well suited for intermittent regulation of therapeutic transgenes over short or long time periods.
Journal of Hematotherapy Amp Stem Cell Research, Nov 1, 2002
Several lines of evidence suggest a potential major role for interferon (IFN) in controlling HIV-... more Several lines of evidence suggest a potential major role for interferon (IFN) in controlling HIV-1 replication. However, this inhibition is moderate and is reversible upon IFN removal. To achieve prolonged high concentrations of IFN at the site of infection, we devised an SV40-based vector, SV[HIVLTR]IFN, to direct the synthesis of human IFN-alpha2, by employing a virus-trans-activated human IFN-alpha2 gene to be transcribed in response to HIV-1 infection. Expression of IFN-alpha2 was confirmed by Northern and Western blotting, in SV[HIVLTR]IFN-transduced, HIV-1-challenged human lymphocyte lines and primary human lymphocytes. SV[HIVLTR]IFN-transduced cells showed no evidence of HIV-1-related cytophatic effects when challenged with high doses of HIV-1(NL4-3). As measured by supernatant HIV-1 p24 antigen concentration, IFN-alpha2-expressing cell lines and peripheral blood lymphocytes (PBL) were protected from high-dose challenges of HIV-1. rSV40-delivered IFN-alpha2 inhibited gp120 protein synthesis and expression of HIV-1 mRNAs. Finally, Southern analysis revealed that levels of proviral DNA were markedly reduced in SV[HIVLTR]IFN-transduced cells compared to control cultures. IFN-alpha2 expression driven by HIVLTR delivered by an rSV40 vector thus strongly inhibits HIV-1 replication, probably by blocking a preintegration step in HIV-1 infection. Targeted expression of IFN-alpha2 delivered by SV40 can thus repress HIV-1 replication, and may be a useful approach to HIV-1 treatment.
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Papers by Pierre Cordelier