50 results on '"Sophie Viaud"'
Search Results
2. Human CD19-specific switchable CAR T-cells are efficacious as constitutively active CAR T-cells but cause less morbidity in a mouse model of human CD19+ malignancy
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Travis S Young, Mark J Osborn, Bruce R Blazar, Michael Jensen, Christopher A Pennell, Heather Campbell, Sophie Viaud, Meghan D Storlie, Sara Bolivar-Wagers, and Yosef Refaeli
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Current Food and Drug Administration (FDA)-approved CD19-specific chimeric antigen receptor (CAR) T-cell therapies for B-cell malignancies are constitutively active and while efficacious, can cause morbidity and mortality. Their toxicities might be reduced if CAR T-cell activity was regulatable rather than constitutive. To test this, we compared the efficacies and morbidities of constitutively active (conventional) and regulatable (switchable) CAR (sCAR) T-cells specific for human CD19 (huCD19) in an immune-competent huCD19+ transgenic mouse model.Conventional CAR (CAR19) and sCAR T-cells were generated by retrovirally transducing C57BL/6 (B6) congenic T-cells with constructs encoding antibody-derived single chain Fv (sFv) fragments specific for huCD19 or a peptide neoepitope (PNE), respectively. Transduced T-cells were adoptively transferred into huCD19 transgenic hemizygous (huCD19Tg/0) B6 mice; healthy B-cells in these mice expressed huCD19Tg. Prior to transfer, recipients were treated with a lymphodepleting dose of cyclophosphamide to enhance T-cell engraftment. In tumor therapy experiments, CAR19 or sCAR T-cells were adoptively transferred into huCD19Tg/0 mice bearing a syngeneic B-cell lymphoma engineered to express huCD19. To regulate sCAR T cell function, a switch protein was generated that contained the sCAR-specific PNE genetically fused to an anti-huCD19 Fab fragment. Recipients of sCAR T-cells were injected with the switch to link sCAR effector with huCD19+ target cells. Mice were monitored for survival, tumor burden (where appropriate), morbidity (as measured by weight loss and clinical scores), and peripheral blood lymphocyte frequency.CAR19 and sCAR T-cells functioned comparably regarding in vivo expansion and B-cell depletion. However, sCAR T-cells were better tolerated as evidenced by the recipients’ enhanced survival, reduced weight loss, and improved clinical scores. Discontinuing switch administration allowed healthy B-cell frequencies to return to pretreatment levels.In our mouse model, sCAR T-cells killed huCD19+ healthy and malignant B-cells and were better tolerated than CAR19 cells. Our data suggest sCAR might be clinically superior to the current FDA-approved therapies for B-cell lymphomas due to the reduced acute and chronic morbidities and mortality, lower incidence and severity of side effects, and B-cell reconstitution on cessation of switch administration.
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- 2022
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3. Dendritic cell-derived exosomes promote natural killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha.
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Sophie Viaud, Magali Terme, Caroline Flament, Julien Taieb, Fabrice André, Sophie Novault, Bernard Escudier, Caroline Robert, Sophie Caillat-Zucman, Thomas Tursz, Laurence Zitvogel, and Nathalie Chaput
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Medicine ,Science - Abstract
Dendritic cell (DC) derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes promoting T cell-dependent tumor rejection. In the first Phase I trial using peptide-pulsed Dex, the observation of clinical regressions in the absence of T cell responses prompted the search for alternate effector mechanisms. Mouse studies unraveled the bioactivity of Dex on NK cells. Indeed, Dex promoted an IL-15Ralpha- and NKG2D-dependent NK cell proliferation and activation respectively, resulting in anti-metastatic effects mediated by NK1.1(+) cells. In humans, Dex express functional IL-15Ralpha which allow proliferation and IFNgamma secretion by NK cells. In contrast to immature DC, human Dex harbor NKG2D ligands on their surface leading to a direct engagement of NKG2D and NK cell activation ex vivo. In our phase I clinical trial, we highlight the capacity of Dex based-vaccines to restore the number and NKG2D-dependent function of NK cells in 7/14 patients. Altogether, these data provide a mechanistic explanation on how Dex may stimulate non MHC restricted-anti-tumor effectors and induce tumor regression in vivo.
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- 2009
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4. Data from Cancer-Induced Immunosuppression: IL-18–Elicited Immunoablative NK Cells
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Laurence Zitvogel, Nathalie Chaput, Mariapia Degli-Esposti, Guido Kroemer, Eric Tartour, Joachim L. Schultze, Masashi Kato, Armelle Prévost-Blondel, Gilles Kaplanski, Salaheddine Mécheri, Lieping Chen, Hideo Yagita, Bernard Ryffel, Sophie Viaud, François Ghiringhelli, Mélanie Desbois, Jérôme D. Coudert, Kathrin Meinhardt, Laetitia Aymeric, Evelyn Ullrich, and Magali Terme
- Abstract
During cancer development, a number of regulatory cell subsets and immunosuppressive cytokines subvert adaptive immune responses. Although it has been shown that tumor-derived interleukin (IL)-18 participates in the PD-1–dependent tumor progression in NK cell–controlled cancers, the mechanistic cues underlying this immunosuppression remain unknown. Here, we show that IL-18 converts a subset of Kit− (CD11b−) into Kit+ natural killer (NK) cells, which accumulate in all lymphoid organs of tumor bearers and mediate immunoablative functions. Kit+ NK cells overexpressed B7-H1/PD-L1, a ligand for PD-1. The adoptive transfer of Kit+ NK cells promoted tumor growth in two pulmonary metastases tumor models and significantly reduced the dendritic and NK cell pools residing in lymphoid organs in a B7-H1–dependent manner. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18–binding protein dramatically reduced the accumulation of Kit+CD11b− NK cells in tumor bearers. Together, our findings show that IL-18 produced by tumor cells elicits Kit+CD11b− NK cells endowed with B7-H1–dependent immunoablative functions in mice. Cancer Res; 72(11); 2757–67. ©2012 AACR.
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- 2023
5. Data from Opposing Effects of Toll-like Receptor (TLR3) Signaling in Tumors Can Be Therapeutically Uncoupled to Optimize the Anticancer Efficacy of TLR3 Ligands
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Laurence Zitvogel, Guido Kroemer, Fabrice André, Nathalie Chaput, Christophe Combadière, Robert Schreiber, Ravindra Uppaluri, Maria Ferrantini, Bernard Ryffel, Sophie Viaud, Magali Terme, Carine Paturel, Yannis Morel, Yuting Ma, and Rosa Conforti
- Abstract
Many cancer cells express Toll-like receptors (TLR) that offer possible therapeutic targets. Polyadenylic-polyuridylic acid [poly(A:U)] is an agonist of the Toll-like receptor TLR3 that displays anticancer properties. In this study, we illustrate how the immunostimulatory and immunosuppressive effects of this agent can be uncoupled to therapeutic advantage. We took advantage of two TLR3-expressing tumor models that produced large amounts of CCL5 (a CCR5 ligand) and CXCL10 (a CXCR3 ligand) in response to type I IFN and poly(A:U), both in vitro and in vivo. Conventional chemotherapy or in vivo injection of poly(A:U), alone or in combination, failed to reduce tumor growth unless an immunochemotherapeutic regimen of vaccination against tumor antigens was included. CCL5 blockade improved the efficacy of immunochemotherapy, whereas CXCR3 blockade abolished its beneficial effects. These findings show how poly(A:U) can elicit production of a range of chemokines by tumor cells that reinforce immunostimulatory or immunosuppressive effects. Optimizing the anticancer effects of TLR3 agonists may require manipulating these chemokines or their receptors. Cancer Res; 70(2); 490–500
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- 2023
6. Supplementary Figure 1 from Cancer-Induced Immunosuppression: IL-18–Elicited Immunoablative NK Cells
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Laurence Zitvogel, Nathalie Chaput, Mariapia Degli-Esposti, Guido Kroemer, Eric Tartour, Joachim L. Schultze, Masashi Kato, Armelle Prévost-Blondel, Gilles Kaplanski, Salaheddine Mécheri, Lieping Chen, Hideo Yagita, Bernard Ryffel, Sophie Viaud, François Ghiringhelli, Mélanie Desbois, Jérôme D. Coudert, Kathrin Meinhardt, Laetitia Aymeric, Evelyn Ullrich, and Magali Terme
- Abstract
PDF file - 87K, Kit+ CD11b- NK cells expand in lymphoid organs of mice bearing different types of tumors
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- 2023
7. Supplementary Figure 3 from Cancer-Induced Immunosuppression: IL-18–Elicited Immunoablative NK Cells
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Laurence Zitvogel, Nathalie Chaput, Mariapia Degli-Esposti, Guido Kroemer, Eric Tartour, Joachim L. Schultze, Masashi Kato, Armelle Prévost-Blondel, Gilles Kaplanski, Salaheddine Mécheri, Lieping Chen, Hideo Yagita, Bernard Ryffel, Sophie Viaud, François Ghiringhelli, Mélanie Desbois, Jérôme D. Coudert, Kathrin Meinhardt, Laetitia Aymeric, Evelyn Ullrich, and Magali Terme
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PDF file - 119K, Kit signaling is not involved in Kit+ NK cell differentiation and survival
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- 2023
8. Supplementary Figure Legends 1-6 from Opposing Effects of Toll-like Receptor (TLR3) Signaling in Tumors Can Be Therapeutically Uncoupled to Optimize the Anticancer Efficacy of TLR3 Ligands
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Laurence Zitvogel, Guido Kroemer, Fabrice André, Nathalie Chaput, Christophe Combadière, Robert Schreiber, Ravindra Uppaluri, Maria Ferrantini, Bernard Ryffel, Sophie Viaud, Magali Terme, Carine Paturel, Yannis Morel, Yuting Ma, and Rosa Conforti
- Abstract
Supplementary Figure Legends 1-6 from Opposing Effects of Toll-like Receptor (TLR3) Signaling in Tumors Can Be Therapeutically Uncoupled to Optimize the Anticancer Efficacy of TLR3 Ligands
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- 2023
9. Supplementary Figures 1-6 from Opposing Effects of Toll-like Receptor (TLR3) Signaling in Tumors Can Be Therapeutically Uncoupled to Optimize the Anticancer Efficacy of TLR3 Ligands
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Laurence Zitvogel, Guido Kroemer, Fabrice André, Nathalie Chaput, Christophe Combadière, Robert Schreiber, Ravindra Uppaluri, Maria Ferrantini, Bernard Ryffel, Sophie Viaud, Magali Terme, Carine Paturel, Yannis Morel, Yuting Ma, and Rosa Conforti
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Supplementary Figures 1-6 from Opposing Effects of Toll-like Receptor (TLR3) Signaling in Tumors Can Be Therapeutically Uncoupled to Optimize the Anticancer Efficacy of TLR3 Ligands
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- 2023
10. Supplementary Figure 2 from Cyclophosphamide Induces Differentiation of Th17 Cells in Cancer Patients
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Laurence Zitvogel, Nathalie Chaput, Caroline Robert, Philippe Vielh, Virginie Marty, Jean-Charles Soria, Vincent Ribrag, Axel LeCesne, Patricia Pautier, Mustapha Zoubir, Caroline Flament, and Sophie Viaud
- Abstract
Supplementary Figure 2 from Cyclophosphamide Induces Differentiation of Th17 Cells in Cancer Patients
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- 2023
11. Supplementary Figure 2 from Cancer-Induced Immunosuppression: IL-18–Elicited Immunoablative NK Cells
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Laurence Zitvogel, Nathalie Chaput, Mariapia Degli-Esposti, Guido Kroemer, Eric Tartour, Joachim L. Schultze, Masashi Kato, Armelle Prévost-Blondel, Gilles Kaplanski, Salaheddine Mécheri, Lieping Chen, Hideo Yagita, Bernard Ryffel, Sophie Viaud, François Ghiringhelli, Mélanie Desbois, Jérôme D. Coudert, Kathrin Meinhardt, Laetitia Aymeric, Evelyn Ullrich, and Magali Terme
- Abstract
PDF file - 105K, IL-18 does not promote the proliferation of Kit+ NK cells in vivo
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- 2023
12. Supplementary Figure Legends from Cyclophosphamide Induces Differentiation of Th17 Cells in Cancer Patients
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Laurence Zitvogel, Nathalie Chaput, Caroline Robert, Philippe Vielh, Virginie Marty, Jean-Charles Soria, Vincent Ribrag, Axel LeCesne, Patricia Pautier, Mustapha Zoubir, Caroline Flament, and Sophie Viaud
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Supplementary Figure Legends from Cyclophosphamide Induces Differentiation of Th17 Cells in Cancer Patients
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- 2023
13. Supplementary Table 1 from Cancer-Induced Immunosuppression: IL-18–Elicited Immunoablative NK Cells
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Laurence Zitvogel, Nathalie Chaput, Mariapia Degli-Esposti, Guido Kroemer, Eric Tartour, Joachim L. Schultze, Masashi Kato, Armelle Prévost-Blondel, Gilles Kaplanski, Salaheddine Mécheri, Lieping Chen, Hideo Yagita, Bernard Ryffel, Sophie Viaud, François Ghiringhelli, Mélanie Desbois, Jérôme D. Coudert, Kathrin Meinhardt, Laetitia Aymeric, Evelyn Ullrich, and Magali Terme
- Abstract
PDF file - 297K, Differentially expressed genes between Kit+ and Kit- samples, FC >2, p-value 100
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- 2023
14. Supplementary Figure 1 from Cyclophosphamide Induces Differentiation of Th17 Cells in Cancer Patients
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Laurence Zitvogel, Nathalie Chaput, Caroline Robert, Philippe Vielh, Virginie Marty, Jean-Charles Soria, Vincent Ribrag, Axel LeCesne, Patricia Pautier, Mustapha Zoubir, Caroline Flament, and Sophie Viaud
- Abstract
Supplementary Figure 1 from Cyclophosphamide Induces Differentiation of Th17 Cells in Cancer Patients
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- 2023
15. Supplementary Figure 4 from Cancer-Induced Immunosuppression: IL-18–Elicited Immunoablative NK Cells
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Laurence Zitvogel, Nathalie Chaput, Mariapia Degli-Esposti, Guido Kroemer, Eric Tartour, Joachim L. Schultze, Masashi Kato, Armelle Prévost-Blondel, Gilles Kaplanski, Salaheddine Mécheri, Lieping Chen, Hideo Yagita, Bernard Ryffel, Sophie Viaud, François Ghiringhelli, Mélanie Desbois, Jérôme D. Coudert, Kathrin Meinhardt, Laetitia Aymeric, Evelyn Ullrich, and Magali Terme
- Abstract
PDF file - 111K, Phenotypic features of Kit+ NK cells compared with Kit- NK cells
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- 2023
16. Supplementary Figure 1 from IL-18 Induces PD-1–Dependent Immunosuppression in Cancer
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Laurence Zitvogel, Nathalie Chaput, Guido Kroemer, Eric Tartour, Joachim L. Schultze, Masashi Kato, Armelle Prévost-Blondel, Gilles Kaplanski, Hideo Yagita, Bernard Ryffel, Sophie Viaud, Nicolas Delahaye, Mélanie Desbois, Kathrin Meinhardt, Laetitia Aymeric, Evelyn Ullrich, and Magali Terme
- Abstract
Supplementary Figure 1 from IL-18 Induces PD-1–Dependent Immunosuppression in Cancer
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- 2023
17. Supplementary Figure Legends 1-4 from Cancer-Induced Immunosuppression: IL-18–Elicited Immunoablative NK Cells
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Laurence Zitvogel, Nathalie Chaput, Mariapia Degli-Esposti, Guido Kroemer, Eric Tartour, Joachim L. Schultze, Masashi Kato, Armelle Prévost-Blondel, Gilles Kaplanski, Salaheddine Mécheri, Lieping Chen, Hideo Yagita, Bernard Ryffel, Sophie Viaud, François Ghiringhelli, Mélanie Desbois, Jérôme D. Coudert, Kathrin Meinhardt, Laetitia Aymeric, Evelyn Ullrich, and Magali Terme
- Abstract
PDF file - 98K
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- 2023
18. Supplementary Table 2 from Cancer-Induced Immunosuppression: IL-18–Elicited Immunoablative NK Cells
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Laurence Zitvogel, Nathalie Chaput, Mariapia Degli-Esposti, Guido Kroemer, Eric Tartour, Joachim L. Schultze, Masashi Kato, Armelle Prévost-Blondel, Gilles Kaplanski, Salaheddine Mécheri, Lieping Chen, Hideo Yagita, Bernard Ryffel, Sophie Viaud, François Ghiringhelli, Mélanie Desbois, Jérôme D. Coudert, Kathrin Meinhardt, Laetitia Aymeric, Evelyn Ullrich, and Magali Terme
- Abstract
PDF file - 307K, Differentially expressed genes between Kit+ and Kit- samples, coding for annotated genes, FC >2, p-value 100
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- 2023
19. Supplementary Figure 2 from IL-18 Induces PD-1–Dependent Immunosuppression in Cancer
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Laurence Zitvogel, Nathalie Chaput, Guido Kroemer, Eric Tartour, Joachim L. Schultze, Masashi Kato, Armelle Prévost-Blondel, Gilles Kaplanski, Hideo Yagita, Bernard Ryffel, Sophie Viaud, Nicolas Delahaye, Mélanie Desbois, Kathrin Meinhardt, Laetitia Aymeric, Evelyn Ullrich, and Magali Terme
- Abstract
Supplementary Figure 2 from IL-18 Induces PD-1–Dependent Immunosuppression in Cancer
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- 2023
20. 1205 Treatment of Lupus-prone BXSB Mice with a Modulatable CAR T cell System Targeting CD19
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Ivo Rimann, Hua Huang, Parker Mace, Rosana Gonzalez-Quintial, Eduardo Laborda, Sophie Viaud, Hannah Mora, Argyrios N Theofilopoulos, Travis S Young, and Dwight H Kono
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- 2022
21. Human CD19-specific switchable CAR T-cells are efficacious as constitutively active CAR T-cells but cause less morbidity in a mouse model of human CD19
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Christopher A Pennell, Heather Campbell, Meghan D Storlie, Sara Bolivar-Wagers, Mark J Osborn, Yosef Refaeli, Michael Jensen, Sophie Viaud, Travis S Young, and Bruce R Blazar
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Pharmacology ,Cancer Research ,Oncology ,Immunology ,Molecular Medicine ,Immunology and Allergy - Abstract
Current Food and Drug Administration (FDA)-approved CD19-specific chimeric antigen receptor (CAR) T-cell therapies for B-cell malignancies are constitutively active and while efficacious, can cause morbidity and mortality. Their toxicities might be reduced if CAR T-cell activity was regulatable rather than constitutive. To test this, we compared the efficacies and morbidities of constitutively active (conventional) and regulatable (switchable) CAR (sCAR) T-cells specific for human CD19 (huCD19) in an immune-competent huCD19+transgenic mouse model.Conventional CAR (CAR19) and sCAR T-cells were generated by retrovirally transducing C57BL/6 (B6) congenic T-cells with constructs encoding antibody-derived single chain Fv (sFv) fragments specific for huCD19 or a peptide neoepitope (PNE), respectively. Transduced T-cells were adoptively transferred into huCD19 transgenic hemizygous (huCD19Tg/0) B6 mice; healthy B-cells in these mice expressedhuCD19Tg. Prior to transfer, recipients were treated with a lymphodepleting dose of cyclophosphamide to enhance T-cell engraftment. In tumor therapy experiments, CAR19 or sCAR T-cells were adoptively transferred intohuCD19Tg/0mice bearing a syngeneic B-cell lymphoma engineered to express huCD19. To regulate sCAR T cell function, a switch protein was generated that contained the sCAR-specific PNE genetically fused to an anti-huCD19 Fab fragment. Recipients of sCAR T-cells were injected with the switch to link sCAR effector with huCD19+target cells. Mice were monitored for survival, tumor burden (where appropriate), morbidity (as measured by weight loss and clinical scores), and peripheral blood lymphocyte frequency.CAR19 and sCAR T-cells functioned comparably regarding in vivo expansion and B-cell depletion. However, sCAR T-cells were better tolerated as evidenced by the recipients’ enhanced survival, reduced weight loss, and improved clinical scores. Discontinuing switch administration allowed healthy B-cell frequencies to return to pretreatment levels.In our mouse model, sCAR T-cells killed huCD19+healthy and malignant B-cells and were better tolerated than CAR19 cells. Our data suggest sCAR might be clinically superior to the current FDA-approved therapies for B-cell lymphomas due to the reduced acute and chronic morbidities and mortality, lower incidence and severity of side effects, and B-cell reconstitution on cessation of switch administration.
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- 2022
22. PD-L1 checkpoint blockade delivered by retroviral replicating vector confers anti-tumor efficacy in murine tumor models
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Anthony W. Munday, William P. Accomando, Cynthia Burrascano, Sophie Viaud, Daniel Mendoza, Marin V. Miner, Kader Yagiz, Leah Mitchell, Ali Haghighi, Amy H. Lin, Dawn Gammon, Harry E. Gruber, Douglas J. Jolly, Fernando Lopez Espinoza, Simon Bergqvist, Maria Rodriguez-Aguirre, and Andrew Hofacre
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PD-L1 ,0301 basic medicine ,medicine.drug_class ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,Monoclonal antibody ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,PD-1 ,medicine ,Single-chain variable fragment ,Vector (molecular biology) ,biology ,business.industry ,Immunotherapy ,single chain variable fragment ,retroviral replicating vector ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Cancer research ,immunotherapy ,Antibody ,business ,Research Paper - Abstract
Immune checkpoint inhibitors (CPIs) are associated with a number of immune-related adverse events and low response rates. We provide preclinical evidence for use of a retroviral replicating vector (RRV) selective to cancer cells, to deliver CPI agents that may circumvent such issues and increase efficacy. An RRV, RRV-scFv-PDL1, encoding a secreted single chain variable fragment targeting PD-L1 can effectively compete with PD-1 for PD-L1 occupancy. Cell binding assays showed trans-binding activity on 100% of cells in culture when infection was limited to 5% RRV-scFv-PDL1 infected tumor cells. Further, the ability of scFv PD-L1 to rescue PD-1/PD-L1 mediated immune suppression was demonstrated in a co-culture system consisting of human-derived immune cells and further demonstrated in several syngeneic mouse models including an intracranial tumor model. These tumor models showed that tumors infected with RRV-scFv-PD-L1 conferred robust and durable immune-mediated anti-tumor activity comparable or superior to systemically administered anti-PD-1 or anti PD-L1 monoclonal antibodies. Importantly, the nominal level of scFv-PD-L1 detected in serum is ∼50-150 fold less than reported for systemically administered therapeutic antibodies targeting immune checkpoints. These results support the concept that RRV-scFv-PDL1 CPI strategy may provide an improved safety and efficacy profile compared to systemic monoclonal antibodies of currently approved therapies.
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- 2019
23. Switchable control over in vivo CAR T expansion, B cell depletion, and induction of memory
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Elvira Khialeeva, Lance Sherwood, Ian R. Hardy, Jennifer Ma, Meredith Weglarz, Christopher J. Ackerman, Sung Chang Lee, Sophie Viaud, Brent Benish, Travis S. Young, Eric N. Hampton, Ashley K. Woods, and Vanessa Núñez
- Subjects
Cytotoxicity, Immunologic ,0301 basic medicine ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Antigens, CD19 ,Receptors, Antigen, T-Cell ,Bioengineering ,Biology ,Lymphocyte Activation ,Immunotherapy, Adoptive ,Models, Biological ,memory ,Mice ,03 medical and health sciences ,Immunology and Inflammation ,Immune system ,In vivo ,medicine ,Animals ,cancer ,B cell ,B-Lymphocytes ,Multidisciplinary ,CAR T cell ,Immunotherapy ,Biological Sciences ,medicine.disease ,Phenotype ,Chimeric antigen receptor ,Immunoglobulin Switch Region ,3. Good health ,Mice, Inbred C57BL ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,PNAS Plus ,Models, Animal ,Cancer research ,Cytokines ,Female ,immunotherapy ,control - Abstract
Significance Chimeric antigen receptor (CAR) T cell therapy represents a powerful strategy in immuno-oncology. Nevertheless, associated life-threatening toxicities and chronic B cell aplasia have underscored the need to control engineered T cells in the patient. To address these challenges, we have previously developed a switchable CAR (sCAR) T cell platform that allows dose-titratable control over CAR T cell activity by using antibody-based switches. Here, we demonstrate in a syngeneic murine model that the switchable platform can impart antitumor efficacy while dissociating long-term persistence from chronic B cell aplasia. Further, the functional reversibility of the switchable platform can be leveraged to incorporate “rest” phases through cyclical dosing of the switch to enable the induction of a robust central memory population for in vivo, on-demand expansion of sCAR T cells., Chimeric antigen receptor (CAR) T cells with a long-lived memory phenotype are correlated with durable, complete remissions in patients with leukemia. However, not all CAR T cell products form robust memory populations, and those that do can induce chronic B cell aplasia in patients. To address these challenges, we previously developed a switchable CAR (sCAR) T cell system that allows fully tunable, on/off control over engineered cellular activity. To further evaluate the platform, we generated and assessed different murine sCAR constructs to determine the factors that afford efficacy, persistence, and expansion of sCAR T cells in a competent immune system. We find that sCAR T cells undergo significant in vivo expansion, which is correlated with potent antitumor efficacy. Most importantly, we show that the switch dosing regimen not only allows control over B cell populations through iterative depletion and repopulation, but that the “rest” period between dosing cycles is the key for induction of memory and expansion of sCAR T cells. These findings introduce rest as a paradigm in enhancing memory and improving the efficacy and persistence of engineered T cell products.
- Published
- 2018
24. AI-04 Immunotherapy for lupus in a mouse model to define pathogenesis and therapeutic targeting
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Argyrios N. Theofilopoulos, Travis S. Young, Hua Huang, Dwight H. Kono, and Sophie Viaud
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Systemic lupus erythematosus ,biology ,business.industry ,T cell ,medicine.medical_treatment ,Immunotherapy ,Plasma cell ,medicine.disease ,CD19 ,Immune system ,medicine.anatomical_structure ,Antigen ,Immunology ,biology.protein ,Medicine ,Antibody ,business - Abstract
Background Recent advances in immunotherapy using genetically modified chimeric antigen receptor (CAR) T cells have made it possible to selectively and completely eliminate cells expressing specific cell surface targets. Such a system could potentially be applied to lupus and other autoimmune diseases for identifying new targets in model systems and for therapy. To test the possible utility of such an approach, we therefore conducted a preliminary study to determine the efficacy of anti-CD19 CAR T cell in eliminating B cells and disease development in a spontaneous mouse model of lupus. Methods In these experiments, a modulatable CAR T cell system was used consisting of CAR T cells recognizing an antigenic site on a soluble anti-CD19 Fab ‘switch.’ Thus, activation and killing activity of CAR T cells was dependent on the presence of an independently injected anti-CD19 switch. To study CAR T cell efficacy, lupus-prone male BXSB mice at 3 months of age were initially conditioned with cyclophosphamide i.p., then 24 hour later given CAR T cells and either the anti-CD19 switch or PBS alone every other day (3 mice/group). Mice were followed for mortality, autoantibodies, proteinuria, and peripheral blood and spleen cells populations up to 9 weeks after CAR T cell transfer. Immunoglobulins and autoantibodies in sera were measured by ELISA. Flow cytometry was used to analyze immune cell populations and included a FITC-conjugated switch peptide to identify CAR-expressing T cells. Proteinuria was determined by dipstick and kidney sections were PAS-stained and scored for glomerulonephritis on a 0–4 scale. Results An initial experiment documented that a single i.p. injection of 100 mg/kg of cyclophosphamide at 3 months of age did not reduce the development of lupus in BXSB male mice compared to PBS controls (4 and 3 mice/group). When mice treated with conditioning and CAR T cells were analyzed, the group given anti-CD19 switch but not PBS, had low levels of circulating B cells by one week after CART T cell transfer and for the duration of the experiment. Immunoglobulin and autoantibody levels were present in the PBS group, but undetectable in the anti-CD19 switch group at the end of the 9 week study. All PBS-, but none of the anti-CD19 switch-treated mice group developed severe glomerulonephritis (glomerulonephritis scores: 3.1±0.07 vs 0.43±0.23, p Conclusions In a small study, anti-CD19 CAR T cell treatment of lupus was highly effective in preventing the development of severe lupus glomerulonephritis. Strikingly, at 9 weeks after transfer, there was complete deficiency of circulating immunoglobulins suggesting that long-lived plasma cells either express sufficient levels of CD19 to be targeted by CAR T cells or less likely that the plasma cell population in lupus requires replenishment from newly generated B cells. These findings support the possibility of using the switchable CAR T cell approach to define the role of immune cell subsets in lupus and treatment of severe lupus. Acknowledgements This work was supported by grants from the NHLBI, NIAMS, and NCI.
- Published
- 2018
25. Abstract 4771: The addition of toca 511 and 5-FC to temozolomide improves response in a temozolomide-resistant murine glioblastoma model and correlates with toca 511 dose
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Maria E. Rodriguez-Aguirre, Sophie Viaud, Daniel Mendoza, Tiffany Montellano, Derek G. Ostertag, Harry Gruber, Douglas Jolly, and Cornelia Bentley
- Subjects
Cancer Research ,Oncology - Abstract
Background: Toca 511 (vocimagene amiretrorepvec), an amphotropic retroviral replicating vector (RRV), can successfully and safely deliver a functional, optimized yeast cytosine deaminase (CD) gene to tumors. Within infected cells, CD converts 5-fluorocytosine (5-FC) to the anti-cancer drug 5-fluorouracil (5-FU). The combination of Toca 511 with oral extended release 5-FC (Toca FC), is currently being evaluated in a randomized phase III clinical trial for recurrent high grade glioma (glioblastoma (GBM) and anaplastic astrocytoma) (NCT02414165, Toca 5). Temozolomide (TMZ), in combination with radiation therapy, is the standard of care used for first-line chemotherapy treatment of patients with GBM, the most common and aggressive form of primary brain cancer. Previously, we have shown that: (1) Toca 511/5-FC treatment provides durable response in a syngeneic murine glioma model and supports anti-tumor immune memory; (2) The combination of TMZ and Toca 511/5-FC had synergistic efficacy in a TMZ-sensitive human glioma nude mouse model; (3) TMZ did not inhibit the efficacy of Toca 511/5-FC in a TMZ resistant murine glioma syngeneic model; (4) Toca 511/5-FC caused significant radiosensitization in a radioresistant murine glioma model. Results: To assess the interaction of TMZ with escalating doses of Toca 511 (as defined by percent of tumor transduction by RRV), an orthotopic TMZ-resistant murine glioma model, Tu-2449, was utilized. These results show that moderate levels of tumor transduction of Toca 511 (30% - 50%) with 5-FC treatment prolongs survival in the presence of TMZ compared with lower transduction rates (10%). Additionally, mice treated with Toca 511/5-FC and TMZ are being tested for the establishment of anti-tumor immune memory. Conclusion: These results demonstrate that (1) survival correlates with the transduction levels of Toca 511 when combined with temozolomide in the Tu-2449 orthotopic glioma model and (2) that this combination may support anti-tumor immune memory. These studies along with prior work support evaluation of the combination of Toca 511/5-FC with temozolomide in patients with newly diagnosed GBM (NRG-BN006). Citation Format: Maria E. Rodriguez-Aguirre, Sophie Viaud, Daniel Mendoza, Tiffany Montellano, Derek G. Ostertag, Harry Gruber, Douglas Jolly, Cornelia Bentley. The addition of toca 511 and 5-FC to temozolomide improves response in a temozolomide-resistant murine glioblastoma model and correlates with toca 511 dose [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4771.
- Published
- 2019
26. Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines
- Author
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Marie Vétizou, Pierre Bruhns, Guido Kroemer, Laurence Zitvogel, Mark J. Smyth, Clara Locher, Dalil Hannani, Laetitia Aymeric, D Sanchez, Takahiro Yamazaki, Sophie Viaud, V Colin-Minard, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Institute of Microbiology of the Czech Academy of Sciences [Prague, Czech Republic] (MBU / CAS), Czech Academy of Sciences [Prague] (CAS), University of Southern Queensland (USQ), Anticorps en Thérapie et Pathologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Apoptose, cancer et immunité (U848), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hannani, Dalil, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institute of Microbiology of the Czech Academy of Sciences (MBU / CAS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology ,Fc receptor ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Antineoplastic Agents ,Apoptosis ,Breast Neoplasms ,Receptors, Fc ,Antibodies ,Mice ,Immune system ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Antigen ,Immunity ,Cell Line, Tumor ,Animals ,Humans ,Cytotoxic T cell ,Anthracyclines ,Molecular Biology ,B-Lymphocytes ,Original Paper ,biology ,Sarcoma ,[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy ,Cell Biology ,Middle Aged ,Immunity, Humoral ,3. Good health ,Mice, Inbred C57BL ,Immunology ,Humoral immunity ,biology.protein ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Immunogenic cell death ,Female ,[SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy ,Antibody ,Calreticulin ,T-Lymphocytes, Cytotoxic - Abstract
International audience; Immunogenic cell death induced by cytotoxic compounds contributes to the success of selected chemotherapies by eliciting a protective anticancer immune response, which is mediated by CD4 þ and CD8 þ T cells producing interferon-c. In many instances, cancer progression is associated with high titers of tumor-specific antibodies, which become detectable in the serum, but whose functional relevance is elusive. Here, we explored the role of humoral immune responses in the anticancer efficacy of anthracyclines. Chemotherapy reduced the number of tumor-infiltrating B cells, and failed to promote humoral responses against immunodominant tumor antigens. Although anthracycline-based anticancer chemotherapies failed in T cell-deficient mice, they successfully reduced the growth of cancers developing in mice lacking B lymphocytes (due to the injection of a B-cell-depleting anti-CD20 antibody), immunoglobulins (Igs) or Ig receptors (Fc receptor) due to genetic manipulations. These results suggest that the humoral arm of antitumor immunity is dispensable for the immune-dependent therapeutic effect of anthracyclines against mouse sarcoma. In addition, we show here that the titers of IgA and IgG antibodies directed against an autoantigen appearing at the cell surface of tumor cells post chemotherapy (calreticulin, CRT) did not significantly increase in patients treated with anthracyclines, and that anti-CRT antibodies had no prognostic or predictive significance. Collectively, our data indicate that humoral anticancer immune responses differ from cellular responses in, thus far, that they do not contribute to the success of anthracycline-mediated anticancer therapies in human breast cancers and mouse sarcomas.
- Published
- 2013
27. Cancer-Induced Immunosuppression: IL-18–Elicited Immunoablative NK Cells
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Jérôme D. Coudert, Salaheddine Mécheri, Mariapia A. Degli-Esposti, Lieping Chen, Armelle Prévost-Blondel, Guido Kroemer, Evelyn Ullrich, Masashi Kato, Bernard Ryffel, Eric Tartour, Kathrin Meinhardt, Gilles Kaplanski, Mélanie Desbois, François Ghiringhelli, Laetitia Aymeric, Laurence Zitvogel, Magali Terme, Nathalie Chaput, Hideo Yagita, Joachim L. Schultze, and Sophie Viaud
- Subjects
Cancer Research ,Adoptive cell transfer ,medicine.medical_treatment ,Cell ,Biology ,B7-H1 Antigen ,Mice ,Immune system ,Neoplasms ,medicine ,Animals ,Mice, Inbred BALB C ,CD11b Antigen ,Interleukin-18 ,Interleukin ,Immunosuppression ,Killer Cells, Natural ,Mice, Inbred C57BL ,Proto-Oncogene Proteins c-kit ,Lymphatic system ,medicine.anatomical_structure ,Oncology ,Tumor progression ,Immunology ,Female ,Interleukin 18 - Abstract
During cancer development, a number of regulatory cell subsets and immunosuppressive cytokines subvert adaptive immune responses. Although it has been shown that tumor-derived interleukin (IL)-18 participates in the PD-1–dependent tumor progression in NK cell–controlled cancers, the mechanistic cues underlying this immunosuppression remain unknown. Here, we show that IL-18 converts a subset of Kit− (CD11b−) into Kit+ natural killer (NK) cells, which accumulate in all lymphoid organs of tumor bearers and mediate immunoablative functions. Kit+ NK cells overexpressed B7-H1/PD-L1, a ligand for PD-1. The adoptive transfer of Kit+ NK cells promoted tumor growth in two pulmonary metastases tumor models and significantly reduced the dendritic and NK cell pools residing in lymphoid organs in a B7-H1–dependent manner. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18–binding protein dramatically reduced the accumulation of Kit+CD11b− NK cells in tumor bearers. Together, our findings show that IL-18 produced by tumor cells elicits Kit+CD11b− NK cells endowed with B7-H1–dependent immunoablative functions in mice. Cancer Res; 72(11); 2757–67. ©2012 AACR.
- Published
- 2012
28. Cyclophosphamide Induces Differentiation of Th17 Cells in Cancer Patients
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Caroline Flament, Sophie Viaud, Mustapha Zoubir, Vincent Ribrag, Jean-Charles Soria, Nathalie Chaput, Patricia Pautier, Virginie Marty, Caroline Robert, A. Lecesne, Laurence Zitvogel, and Philippe Vielh
- Subjects
Adult ,Male ,Cancer Research ,Cyclophosphamide ,medicine.medical_treatment ,Melanoma, Experimental ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,Piperazines ,Autoimmunity ,Mice ,chemistry.chemical_compound ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Inducer ,Antineoplastic Agents, Alkylating ,Aged ,business.industry ,Melanoma ,Cancer ,Cell Differentiation ,Immunotherapy ,Middle Aged ,medicine.disease ,Lymphocyte Subsets ,Nitrogen mustard ,Mice, Inbred C57BL ,Pyrimidines ,Imatinib mesylate ,Oncology ,chemistry ,Benzamides ,Immunology ,Imatinib Mesylate ,Cancer research ,Interleukin-2 ,Th17 Cells ,Female ,business ,medicine.drug - Abstract
Low doses of the alkylating agent cyclophosphamide (CTX) mediate antiangiogenic and immunostimulatory effects, leading to potent tumoricidal activity in association with various immunotherapeutic strategies. Here, we show in rodents and cancer patients that CTX markedly promotes the differentiation of CD4+ T helper 17 (Th17) cells that can be recovered in both blood and tumor beds. However, CTX does not convert regulatory T cells into Th17 cells. Because Th17 are potent inducers of tissue inflammation and autoimmunity, these results suggest impact on the clinical management of various types of malignancies treated with alkylating agents and a potential need to optimize CTX-based immunotherapy in patients. Cancer Res; 71(3); 661–5. ©2010 AACR.
- Published
- 2011
29. Dendritic Cell-Derived Exosomes for Cancer Immunotherapy: What's Next?
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Stéphanie Ploix, Thomas Tursz, Olivier Lantz, Nathalie Chaput, Clotilde Théry, Laurence Zitvogel, Sophie Viaud, and Valérie Lapierre
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Cancer Research ,Lung Neoplasms ,medicine.medical_treatment ,Exosomes ,Cancer Vaccines ,Immunotherapy, Adoptive ,Models, Biological ,Exosome ,Immune system ,Cancer immunotherapy ,Carcinoma, Non-Small-Cell Lung ,Neoplasms ,medicine ,Animals ,Humans ,Antigen-presenting cell ,Clinical Trials as Topic ,business.industry ,Cancer ,Dendritic Cells ,Dendritic cell ,Immunotherapy ,medicine.disease ,Microvesicles ,Oncology ,Immunology ,Cancer research ,business - Abstract
Exosomes are nanovesicles originating from late endosomal compartments and secreted by most living cells in ex vivo cell culture conditions. The interest in exosomes was rekindled when B-cell and dendritic cell-derived exosomes were shown to mediate MHC-dependent immune responses. Despite limited understanding of exosome biogenesis and physiological relevance, accumulating evidence points to their bioactivity culminating in clinical applications in cancer. This review focuses on the preclinical studies exploiting the immunogenicity of dendritic cell-derived exosomes (Dex) and will elaborate on the past and future vaccination trials conducted using Dex strategy in melanoma and non-small cell lung cancer patients. Cancer Res; 70(4); 1281–5
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- 2010
30. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC
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Alain Livartoski, Melinda Charrier, Ludovic Lacroix, Inka Zoernig, Eric Dansin, Olivier Lantz, Benjamin Besse, Nadege Vimond, Kavita M. Dhodapkar, Jean-Charles Soria, Isabelle Peguillet, Frédéric Vély, Madhav V. Dhodapkar, Elke Pogge von Strandmann, Katrin S. Reiners, Clotilde Théry, Nathalie Chaput, Alexander M.M. Eggermont, Sophie Viaud, Agnès Laplanche, Thierry Le Chevalier, David Planchard, Fabrice Barlesi, Laurence Zitvogel, Valérie Lapierre, Sylvie Rusakiewicz, Stéphanie Ploix, Jonathan M. Pitt, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)
- Subjects
0301 basic medicine ,medicine.medical_treatment ,T cell ,Immunology ,exosomes ,NSCLC ,03 medical and health sciences ,MHC class I ,polycyclic compounds ,Immunology and Allergy ,Medicine ,NK cell ,phase II trial ,Original Research ,MHC class II ,biology ,business.industry ,Induction chemotherapy ,Dendritic cell ,Immunotherapy ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Tumor progression ,biology.protein ,Cancer research ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Cancer vaccine ,immunotherapy ,business ,cancer vaccine ,hormones, hormone substitutes, and hormone antagonists - Abstract
International audience; Dendritic cell-derived exosomes (Dex) are small extracellular vesicles secreted by viable dendritic cells. In the two phase-I trials that we conducted using the first generation of Dex (IFN―free) in end-stage cancer, we reported that Dex exerted natural killer (NK) cell effector functions in patients. A second generation of Dex (IFN―Dex) was manufactured with the aim of boosting NK and T cell immune responses. We carried out a phase II clinical trial testing the clinical benefit of IFN―Dex loaded with MHC class I- and class II-restricted cancer antigens as maintenance immunotherapy after induction chemotherapy in patients bearing inoperable non-small cell lung cancer (NSCLC) without tumor progression. The primary endpoint was to observe at least 50% of patients with progression-free survival (PFS) at 4 mo after chemotherapy cessation. Twenty-two patients received IFN―Dex. One patient exhibited a grade three hepatotoxicity. The median time to progression was 2.2 mo and median overall survival (OS) was 15 mo. Seven patients (32%) experienced stabilization of >4 mo. The primary endpoint was not reached. An increase in NKp30-dependent NK cell functions were evidenced in a fraction of these NSCLC patients presenting with defective NKp30 expression. Importantly, MHC class II expression levels of the final IFN―Dex product correlated with expression levels of the NKp30 ligand BAG6 on Dex, and with NKp30-dependent NK functions, the latter being associated with longer progression-free survival. This phase II trial confirmed the capacity of Dex to boost the NK cell arm of antitumor immunity in patients with advanced NSCLC.
- Published
- 2015
31. Cancer and the gut microbiota: an unexpected link
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Lorenzo Galluzzi, Romain Daillère, Miriam Merad, Guido Kroemer, Sophie Viaud, Marie Vétizou, and Laurence Zitvogel
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Carcinogenesis ,Microbiota ,Gut–brain axis ,Cancer ,Antineoplastic Agents ,General Medicine ,Biology ,Gut flora ,medicine.disease ,medicine.disease_cause ,biology.organism_classification ,Intestinal epithelium ,digestive system ,Article ,Gastrointestinal Tract ,Immune system ,Tumor progression ,Neoplasms ,Immunology ,medicine ,Dysbiosis ,Humans - Abstract
Changes in the interactions among the gut microbiota, intestinal epithelium, and host immune system are associated with many diseases, including cancer. We discuss how environmental factors influence this cross-talk during oncogenesis and tumor progression and how manipulations of the gut microbiota might improve the clinical activity of anticancer agents.
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- 2015
32. Gut microbiome and anticancer immune response: really hot Sh(star)t!
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Romain Daillère, Mikael J. Pittet, François Ghiringhelli, Laurence Zitvogel, Sophie Viaud, Ivo G Boneca, Giorgio Trinchieri, Patricia Lepage, Philippe Langella, Romina S. Goldszmid, Mathias Chamaillard, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris], Groupe Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Centre d’Infection et d’Immunité de Lille (CIIL) - U1019 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre for System Biology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Cancer and Inflammation Program [NCI], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Centre d'Investigation Clinique Biothérapie (CICBT), Institut National du Cancer (INCa) Ligue contre le cancer (LIGUE labellisee) SIRIC Socrate LABEX PACRI Onco-Immunology European Research Council 202283 ISREC Foundation, ANR-11-PHUC-0002/11-PHUC-0002,PACRI,PACRI(2011), European Project: 202283,EC:FP7:ERC,ERC-2007-StG,PGNFROMSHAPETOVIR(2008), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), ANR-11-PHUC-0002,PACRI,Alliance Parisienne des Instituts de Recherche en Cancérologie(2011), Institut Pasteur [Paris] (IP), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Cyclophosphamide ,medicine.drug_class ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Antibiotics ,Antineoplastic Agents ,Review ,Biology ,Gut flora ,Inflammatory bowel disease ,GERM-FREE MICE ,COLORECTAL-CANCER ,Mice ,Immune system ,LUNG-CANCER ,Neoplasms ,medicine ,Animals ,Humans ,Intestinal Mucosa ,Molecular Biology ,TOLL-LIKE RECEPTORS ,Chemotherapy ,Tumor microenvironment ,INDUCED COLITIS ,Innate immune system ,Microbiota ,Cell Biology ,medicine.disease ,biology.organism_classification ,3. Good health ,Anti-Bacterial Agents ,Intestines ,COLON TUMORIGENESIS ,Immunology ,INNATE IMMUNITY ,Th17 Cells ,INTESTINAL EPITHELIAL-CELLS ,BETA-GLUCURONIDASE ,medicine.drug ,INFLAMMATORY-BOWEL-DISEASE - Abstract
The impact of gut microbiota in eliciting innate and adaptive immune responses beneficial for the host in the context of effective therapies against cancer has been highlighted recently. Chemotherapeutic agents, by compromising, to some extent, the intestinal integrity, increase the gut permeability and selective translocation of Gram-positive bacteria in secondary lymphoid organs. There, anticommensal pathogenic Th17 T-cell responses are primed, facilitating the accumulation of Th1 helper T cells in tumor beds after chemotherapy as well as tumor regression. Importantly, the redox equilibrium of myeloid cells contained in the tumor microenvironment is also influenced by the intestinal microbiota. Hence, the anticancer efficacy of alkylating agents (such as cyclophosphamide) and platinum salts (oxaliplatin, cis-platin) is compromised in germ-free mice or animals treated with antibiotics. These findings represent a paradigm shift in our understanding of the mode of action of many compounds having an impact on the host-microbe mutualism.
- Published
- 2015
33. Selective Resistance of Tetraploid Cancer Cells against DNA Damage-Induced Apoptosis
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Laurence Zitvogel, Arnaud Coquelle, Ilio Vitale, Maria Castedo, Guido Kroemer, Shahul Mouhamad, Sophie Viaud, and Sonia Vivet
- Subjects
Genome instability ,Programmed cell death ,Ultraviolet Rays ,DNA damage ,Fluorescent Antibody Technique ,Antineoplastic Agents ,Apoptosis ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Polyploidy ,History and Philosophy of Science ,Cell Line, Tumor ,Chromosome instability ,medicine ,Humans ,Cisplatin ,General Neuroscience ,fungi ,food and beverages ,Molecular biology ,Killer Cells, Natural ,Colonic Neoplasms ,Cancer cell ,Camptothecin ,DNA Damage ,medicine.drug - Abstract
Aneuploidy and chromosomal instability, which are frequent in cancer, can result from the asymmetric division of tetraploid precursors. Genomic instability may favor the generation of more aggressive tumor cells with a reduced propensity for undergoing apoptosis. To assess the impact of tetraploidization on apoptosis regulation, we generated a series of stable tetraploid HCT116 and RKO colon carcinoma cell lines. When comparing diploid parental cells with tetraploid clones, we found that such cells were equally sensitive to a series of cytotoxic agents (staurosporine [STS], hydroxyurea, etoposide), as well as to the lysis by natural killer cells. In strict contrast, tetraploid cells were found to be relatively resistant against a series of DNA-damaging agents, namely cisplatin, oxaliplatin, camptothecin, and gamma- and UVC-irradiation. This increased resistance correlated with a reduced manifestation of apoptotic parameters (such as the dissipation of the mitochondrial transmembrane potential and the degradation of nuclear DNA) in tetraploid as compared to diploid cells subjected to DNA damage. Moreover, tetraploid cells manifested an enhanced baseline level of p53 activation. Inhibition of p53 abolished the difference in the susceptibility of diploid and tetraploid cancer cells to DNA damage-induced apoptosis. These data point to an intrinsic resistance of tetraploid cells against radiotherapy and DNA-targeted chemotherapy that may be linked to the status of the p53 system.
- Published
- 2006
34. Macrophage activation switching: an asset for the resolution of inflammation
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Cathie Léone, Gabriel Gras, Dominique Dormont, Fabrice Porcheray, Anne-Cécile Rimaniol, Sophie Viaud, Nathalie Dereuddre-Bosquet, and Boubekeur Samah
- Subjects
Cell Survival ,medicine.medical_treatment ,Immunology ,Cell ,Anti-Inflammatory Agents ,Antigens, Differentiation, Myelomonocytic ,CCL3 ,Receptors, Cell Surface ,Inflammation ,Biology ,Monocytes ,Proinflammatory cytokine ,Phagocytosis ,Basic Immunology ,Antigens, CD ,medicine ,Humans ,Immunology and Allergy ,Macrophage ,Lectins, C-Type ,Chemokine CCL4 ,Cells, Cultured ,Chemokine CCL3 ,Macrophages ,CCL18 ,HLA-DR Antigens ,Immunotherapy ,Macrophage Activation ,Macrophage Inflammatory Proteins ,Flow Cytometry ,Mannose-Binding Lectins ,Phenotype ,medicine.anatomical_structure ,Chemokines, CC ,Cytokines ,medicine.symptom ,CD163 ,Mannose Receptor - Abstract
SummaryMacrophages play a central role in inflammation and host defence against microorganisms, but they also participate actively in the resolution of inflammation after alternative activation. However, it is not known whether the resolution of inflammation requires alternative activation of new resting monocytes/macrophages or if proinflammatory activated macrophages have the capacity to switch their activation towards anti-inflammation. In order to answer this question, we first characterized differential human macrophage activation phenotypes. We found that CD163 and CD206 exhibited mutually exclusive induction patterns after stimulation by a panel of anti-inflammatory molecules, whereas CCL18 showed a third, overlapping, pattern. Hence, alternative activation is not a single process, but provides a variety of different cell populations. The capacity of macrophages to switch from one activation state to another was then assessed by determining the reversibility of CD163 and CD206 expression and of CCL18 and CCL3 production. We found that every activation state was rapidly and fully reversible, suggesting that a given cell may participate sequentially in both the induction and the resolution of inflammation. These findings may provide new insight into the inflammatory process as well as new fields of investigation for immunotherapy in the fields of chronic inflammatory diseases and cancer.
- Published
- 2005
35. Dendritic cell-derived exosomes as immunotherapies in the fight against cancer
- Author
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Benjamin Besse, Fabrice Andre, Nathalie Chaput, Melinda Charrier, Laurence Zitvogel, Sophie Viaud, and Jonathan M. Pitt
- Subjects
Cell type ,Endosome ,Immunology ,chemical and pharmacologic phenomena ,Biology ,Exosomes ,Cancer Vaccines ,Mice ,Immune system ,medicine ,Tumor Cells, Cultured ,Immunology and Allergy ,Animals ,Humans ,Molecular Targeted Therapy ,Clinical Trials as Topic ,Cancer ,Dendritic cell ,Dendritic Cells ,Neoplasms, Experimental ,medicine.disease ,Microvesicles ,Disease Models, Animal ,Tumor rejection ,Cancer research ,Immunotherapy ,Intracellular - Abstract
Exosomes are nanometric membrane vesicles of late endosomal origin released by most, if not all, cell types as a means of sophisticated intercellular communication. A multitude of studies showed how exosomes can mediate and regulate immune responses against tumors. Dendritic cell–derived exosomes (Dex) have received much attention as immunotherapeutic anticancer agents since the discovery that they harbor functional MHC–peptide complexes, in addition to various other immune-stimulating components, that together facilitate immune cell–dependent tumor rejection. The therapeutic potential of Dex has been substantiated with their development and clinical testing in the treatment of cancer. This review focuses on mechanisms by which Dex interact with and influence immune cells and describes how they can be engineered to promote their immunogenic capacity as novel and dynamic anticancer agents.
- Published
- 2014
36. The role of the microbiota in inflammation, carcinogenesis, and cancer therapy
- Author
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Giorgio Trinchieri, Laurence Zitvogel, Amiran Dzutsev, Romina S. Goldszmid, and Sophie Viaud
- Subjects
Carcinogenesis ,Immunology ,Inflammation ,Antineoplastic Agents ,Biology ,Adaptive Immunity ,medicine.disease_cause ,Microbiology ,Autoimmune Diseases ,Immunomodulation ,Mice ,Immune system ,Immunity ,Neoplasms ,medicine ,Immunology and Allergy ,Animals ,Humans ,Symbiosis ,Host (biology) ,Microbiota ,Cancer ,Acquired immune system ,medicine.disease ,Biological Evolution ,Immunity, Innate ,Tumor Escape ,Metagenome ,medicine.symptom - Abstract
Commensal microorganisms colonize barrier surfaces of all multicellular organisms, including those of humans. For more than 500 million years, commensal microorganisms and their hosts have coevolved and adapted to each other. As a result, the commensal microbiota affects many immune and nonimmune functions of their hosts, and de facto the two together comprise one metaorganism. The commensal microbiota communicates with the host via biologically active molecules. Recently, it has been reported that microbial imbalance may play a critical role in the development of multiple diseases, such as cancer, autoimmune conditions, and increased susceptibility to infection. In this review, we focus on the role of the commensal microbiota in the development, progression, and immune evasion of cancer, as well as some modulatory effects on the treatment of cancer. In particular, we discuss the mechanisms of microbiota-mediated regulation of innate and adaptive immune responses to tumors, and the consequences on cancer progression and whether tumors subsequently become resistant or susceptible to different anticancer therapeutic regiments.
- Published
- 2014
37. Why should we need the gut microbiota to respond to cancer therapies?
- Author
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Giorgio Trinchieri, Sophie Viaud, Patricia Lepage, Laurence Zitvogel, Romain Daillère, Romina S. Goldszmid, Takahiro Yamazaki, Ivo G Boneca, ProdInra, Archive Ouverte, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Groupe Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris] (IP), Cancer and Inflammation Program, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Institut Pasteur [Paris], and Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
pTh17 ,Cyclophosphamide ,medicine.drug_class ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Immunology ,Antibiotics ,Gut flora ,chemotherapy ,antibiotics ,antibiotique ,immunomodulateur ,microbiote ,medicine ,chimiothérapie ,microbiota ,Immunology and Allergy ,cancer ,Author's View ,immunomodulatory regimen ,Chemotherapy ,biology ,Effector ,business.industry ,Cancer ,Gram-positive bacteria ,medicine.disease ,biology.organism_classification ,3. Good health ,[SDV] Life Sciences [q-bio] ,Oncology ,Intestinal bacteria ,business ,bactérie gram positif ,medicine.drug - Abstract
Cyclophosphamide, one of the most efficient tumoricidal, antiangiogenic, and immunostimulatory drugs employed to date mediates part of its effects through intestinal bacteria, against which the host becomes immunized during treatment. Our recent work suggests that anti-commensal effector pT(H)17 and memory T(H)1 CD4(+) T-cell responses are indispensable for optimal anticancer effects as mediated by cyclophosphamide.
- Published
- 2014
38. Harnessing the intestinal microbiome for optimal therapeutic immunomodulation
- Author
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François Ghiringhelli, Giorgio Trinchieri, Romina S. Goldszmid, Romain Daillère, Laurence Zitvogel, Mikael J. Pittet, Patricia Lepage, Sophie Viaud, Ivo G Boneca, Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Institut Pasteur [Paris], Grp Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Center for Systems Biology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Cancer Inflammation Program [Frederick], Center for Cancer Research, Canc & Inflammat Program, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), CICBT 507, Centre d'Investigation Clinique Biothérapie (CICBT), Institut National du Cancer (INCa), la Ligue contre le cancer (LIGUE labellisee), SIRIC Socrate, LABEX and PACRI Onco-Immunology, European Research Council starting grant (PGNfromSHAPEtoVIR no202283, to I. G. Boneca), and the ISREC Foundation., European Project: 202283,EC:FP7:ERC,ERC-2007-StG,PGNFROMSHAPETOVIR(2008), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), ProdInra, Archive Ouverte, and The role of peptidoglycan in bacterial cell physiology: from bacterial shape to host-microbe interactions - PGNFROMSHAPETOVIR - - EC:FP7:ERC2008-08-01 - 2013-07-31 - 202283 - VALID
- Subjects
Cancer Research ,Microbiota/immunology ,Cyclophosphamide ,Lipopolysaccharide ,IMPACT ,HUMAN GUT MICROBIOME ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Immunomodulation/immunology ,Article ,Immunomodulation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,RICHNESS ,CYCLOPHOSPHAMIDE ,medicine ,Animals ,Humans ,REGULATORY T-CELLS ,Cytotoxicity ,030304 developmental biology ,Intestines/immunology/microbiology ,0303 health sciences ,Tumor microenvironment ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Bacteria ,Effector ,Microbiota ,TLR9 ,Bacteria/immunology/metabolism ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,Acquired immune system ,GENE ,3. Good health ,Intestines ,[SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Immunology ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,medicine.drug ,Signal Transduction - Abstract
Distinct cytotoxic agents currently used in the oncological armamentarium mediate their clinical benefit by influencing, directly or indirectly, the immune system in such a way that innate and adaptive immunity contributes to the tumoricidal activity. Now, we bring up evidence that both arms of anticancer immunity can be triggered through the intervention of the intestinal microbiota. Alkylating agents, such as cyclophosphamide, set up the stage for enhanced permeability of the small intestine, facilitating the translocation of selected arrays of Gram-positive bacteria against which the host mounts effector pTh17 cells and memory Th1 responses. In addition, gut commensals, through lipopolysaccharide and other bacterial components, switch the tumor microenvironment, in particular the redox equilibrium and the TNF production of intratumoral myeloid cells during therapies with platinum salts or intratumoral TLR9 agonists combined with systemic anti-IL10R Ab respectively. Consequently, antibiotics can compromise the efficacy of certain chemotherapeutic or immunomodulatory regimens. Cancer Res; 74(16); 4217–21. ©2014 AACR.
- Published
- 2014
39. Therapy-Induced Tumor Immunosurveillance Involves IFN-Producing Killer Dendritic Cells
- Author
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Mathieu Bonmort, Laurence Zitvogel, Evelyn Ullrich, Julien Taieb, Cédric Ménard, Guido Kroemer, Thomas Tursz, Grégoire Mignot, Nathalie Chaput, Sophie Viaud, Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépatogastro-entérologie et d'oncologie digestive, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Mignot, Grégoire
- Subjects
Cancer Research ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,MESH: Immunotherapy ,MESH: Interferon-gamma ,medicine.medical_treatment ,MESH: Piperazines ,Antineoplastic Agents ,chemical and pharmacologic phenomena ,Biology ,Piperazines ,Interferon-gamma ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,MESH: Animals ,Antigen-presenting cell ,MESH: Mice ,030304 developmental biology ,0303 health sciences ,Lymphokine-activated killer cell ,Innate immune system ,MESH: Dendritic Cells ,Dendritic Cells ,Neoplasms, Experimental ,Immunotherapy ,Dendritic cell ,Natural killer T cell ,3. Good health ,Immunosurveillance ,Pyrimidines ,MESH: Neoplasms, Experimental ,Imatinib mesylate ,Oncology ,MESH: Pyrimidines ,Benzamides ,Immunology ,Imatinib Mesylate ,MESH: Antineoplastic Agents ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,030215 immunology - Abstract
A unique class of IFN-producing killer dendritic cells (IKDC) resembling natural killer cells has been defined that can recognize and lyse tumor cells through a tumor necrosis factor–related apoptosis-inducing ligand–dependent mechanism. IKDC may mediate the host-dependent antitumor activity of Gleevec/STI571 and other therapeutics that can inhibit the c-kit tyrosine kinase. IKDC represent an important new component of the innate immune system responding to cancer. [Cancer Res 2007;67(3):851–3]
- Published
- 2007
40. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide
- Author
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Christina Pfirschke, Charles O. Elson, Marion Bérard, Florent Ginhoux, Nadine Cerf-Bensussan, Mikael J. Pittet, Fabiana Saccheri, Lionel Apetoh, François Ghiringhelli, Eric Vivier, Elisabeth Chachaty, Guido Kroemer, Paul Louis Woerther, Paule Opolon, Andreas Schlitzer, Valérie Gaboriau-Routhiau, Sophie Viaud, Chantal Bizet, Bernhard Ryffel, Patricia Lepage, Gérard Eberl, Nadia Yessaad, David Enot, Camilla Engblom, Ivo G. Boneca, Grégoire Mignot, Chantal Ecobichon, Romain Daillère, Dalil Hannani, Dominique Clermont, Joël Doré, Laurence Zitvogel, Takahiro Yamazaki, Université Paris-Sud - Paris 11 (UP11), Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Apoptose, cancer et immunité (U848), Harvard Medical School [Boston] (HMS), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Microbiologie, Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Développement des Tissus Lymphoïdes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Animalerie centrale (Plate-forme), Institut Pasteur [Paris], Groupe Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall (BGPB), Collection de l'Institut Pasteur (CIP), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, U989, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR54 IRCIV, Institut de recherche intégrée en cancérologie, Laboratoire de Pathologie Expérimentale, Institut Gustave Roussy (IGR), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), University of Alabama at Birmingham [ Birmingham] (UAB), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Paris, Université Paris Descartes - Paris 5 (UPD5), Groupe Avenir [Dijon], Programme ATIP - Avenir, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National du Cancer (INCa), la Ligue contre le cancer (LIGUE labelisee), SIRIC Socrates, LABEX, PACRI Onco-Immunology, European Research Council [202283], NIH [P01DK071176], ANR-11-PHUC-0002/11-PHUC-0002,PACRI,PACRI(2011), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-11-PHUC-0002,PACRI,Alliance Parisienne des Instituts de Recherche en Cancérologie(2011), ProdInra, Archive Ouverte, Pôle hospitalier Universitaire Cancer (PHUC) - Alliance Parisienne des Instituts de Recherche en Cancérologie - - PACRI2011 - ANR-11-PHUC-0002 - PHUC - VALID, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris-Sud - Paris 11 ( UP11 ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Apoptose, cancer et immunité ( U848 ), Harvard Medical School, Center for Systems Biology, Harvard University-Massachusetts General Hospital ( MGH ), Agency for Science, Technology and Research, Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale, Biologie et Génétique de la Paroi bactérienne, Collection de l'Institut Pasteur ( CIP ), MICrobiologie de l'ALImentation au Service de la Santé humaine ( MICALIS ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Institut National de la Santé et de la Recherche Médicale-Université Paris Descartes - Paris 5 ( UPD5 ), Institut Gustave Roussy ( IGR ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Immunologie et Neurogénétique Expérimentales et Moléculaires ( INEM ), Université d'Orléans ( UO ) -Centre National de la Recherche Scientifique ( CNRS ), The University of Alabama at Birmingham [ Birmingham] ( UAB ), Apoptose, cancer et immunité ( Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138 ), Institut Gustave Roussy ( IGR ) -Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and ANR-11-PHUC-0002/11-PHUC-0002,PACRI,PACRI ( 2011 )
- Subjects
Adoptive cell transfer ,Cyclophosphamide ,medicine.drug_class ,Lymphoid Tissue ,Gram-positive bacteria ,[SDV]Life Sciences [q-bio] ,Antibiotics ,Antineoplastic Agents ,Gut flora ,Gram-Positive Bacteria ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Neoplasms ,Intestine, Small ,medicine ,Tumor Microenvironment ,Germ-Free Life ,Animals ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,biology ,[ SDV ] Life Sciences [q-bio] ,Microbiota ,biology.organism_classification ,Adoptive Transfer ,Small intestine ,3. Good health ,Anti-Bacterial Agents ,Intestines ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,Lymphatic system ,030220 oncology & carcinogenesis ,Bacterial Translocation ,Immunology ,Cancer research ,Th17 Cells ,Immunologic Memory ,Immunosuppressive Agents ,medicine.drug - Abstract
The Microbiota Makes for Good Therapy The gut microbiota has been implicated in the development of some cancers, such as colorectal cancer, but—given the important role our intestinal habitants play in metabolism—they may also modulate the efficacy of certain cancer therapeutics. Iida et al. (p. 967 ) evaluated the impact of the microbiota on the efficacy of an immunotherapy [CpG (the cytosine, guanosine, phosphodiester link) oligonucleotides] and oxaliplatin, a platinum compound used as a chemotherapeutic. Both therapies were reduced in efficacy in tumor-bearing mice that lacked microbiota, with the microbiota important for activating the innate immune response against the tumors. Viaud et al. (p. 971 ) found a similar effect of the microbiota on tumor-bearing mice treated with cyclophosphamide, but in this case it appeared that the microbiota promoted an adaptive immune response against the tumors.
- Published
- 2013
41. Natural nanoparticules against cancer: mature dendritic cell-derived exosomes
- Author
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Sophie Viaud, S Ploix, Laurence Zitvogel, Nathalie Chaput, and M Desbois
- Subjects
Cancer Research ,Oncology ,Chemistry ,Genetics ,medicine ,Cancer ,Hematology ,Dendritic cell ,medicine.disease ,Microvesicles ,Cell biology - Abstract
Deep insight on Natural nanoparticules against cancer: mature dendritic cell-derived exosomes.
- Published
- 2011
42. IL-18 induces PD-1-dependent immunosuppression in cancer
- Author
-
Gilles Kaplanski, Eric Tartour, Joachim L. Schultze, Evelyn Ullrich, Bernhard Ryffel, Nicolas F. Delahaye, Armelle Prévost-Blondel, Guido Kroemer, Laurence Zitvogel, Masashi Kato, Sophie Viaud, Hideo Yagita, Magali Terme, Nathalie Chaput, Laetitia Aymeric, Kathrin Meinhardt, and Mélanie Desbois
- Subjects
Cancer Research ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Melanoma, Experimental ,chemical and pharmacologic phenomena ,Enzyme-Linked Immunosorbent Assay ,Biology ,Immune tolerance ,Mice ,Antigen ,medicine ,Immune Tolerance ,Animals ,Neoplasm Metastasis ,Autoantibodies ,Mice, Inbred BALB C ,Lymphokine-activated killer cell ,Mechanism (biology) ,Melanoma ,Interleukin-18 ,Cancer ,Immunosuppression ,medicine.disease ,Killer Cells, Natural ,Mice, Inbred C57BL ,Oncology ,Immunology ,Antigens, Surface ,Interleukin 18 ,Female ,Apoptosis Regulatory Proteins - Abstract
Immunosuppressive cytokines subvert innate and adaptive immune responses during cancer progression. The inflammatory cytokine interleukin-18 (IL-18) is known to accumulate in cancer patients, but its pathophysiological role remains unclear. In this study, we show that low levels of circulating IL-18, either exogenous or tumor derived, act to suppress the NK cell arm of tumor immunosurveillance. IL-18 produced by tumor cells promotes the development of NK-controlled metastases in a PD-1–dependent manner. Accordingly, PD-1 is expressed by activated mature NK cells in lymphoid organs of tumor bearers and is upregulated by IL-18. RNAi-mediated knockdown of IL-18 in tumors, or its systemic depletion by IL-18–binding protein, are sufficient to stimulate NK cell-dependent immunosurveillance in various tumor models. Together, these results define IL-18 as an immunosuppressive cytokine in cancer. Our findings suggest novel clinical implementations of anti-PD-1 antibodies in human malignancies that produce IL-18. Cancer Res; 71(16); 5393–9. ©2011 AACR.
- Published
- 2011
43. An inhibitor of cyclin-dependent kinases suppresses TLR signaling and increases the susceptibility of cancer patients to herpesviridae
- Author
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Rosa Conforti, Mustapha Zoubir, Nathalie Chaput, Rastilav Bahleda, Laurence Zitvogel, Vassili Soumelis, Abdelaziz Gdoura, Elena Litvinova, Caroline Flament, Jean-Charles Soria, Guido Kroemer, and Sophie Viaud
- Subjects
Adult ,Male ,Cyclin-dependent kinase ,Interferon ,Neoplasms ,medicine ,Humans ,Pyrroles ,Receptor ,Molecular Biology ,Cells, Cultured ,Herpesviridae ,Aged ,biology ,Kinase ,Toll-Like Receptors ,TLR9 ,Cancer ,Cell Biology ,Herpesviridae Infections ,Middle Aged ,medicine.disease ,Cyclin-Dependent Kinases ,TLR3 ,Immunology ,biology.protein ,Cancer research ,Leukocytes, Mononuclear ,Pyrazoles ,Tumor necrosis factor alpha ,Female ,Disease Susceptibility ,Immunosuppressive Agents ,Developmental Biology ,medicine.drug ,Signal Transduction - Abstract
Cyclin-dependent kinase (CDK) inhibitors have been considered as excellent drug candidates for cancer therapy owing to their potential capacity to restore cell cycle control. The first generation of CDK inhibitors showed modest clinical advantages that could be attributed to off-target effects preventing them from reaching therapeutic concentrations. A phase I dose-escalation study using the second generation multi-CDK inhibitor PHA-793887 was conducted on a total of 19 patients with advanced refractory malignancies in two sites in Europe: the University of Leeds and St. James's Institute of Oncology, Leeds, UK, and the Institut Gustave Roussy, Villeujf, France (IGR). Fifteen patients were treated at IGR. Six among these patients manifested the reactivation of herpes virus replication. In vitro experiments revealed that PHA-793887 severely impaired signaling by toll-like receptors (such as TLR3, TLR4 and TLR9) in dendritic cells (DC), thus suppressing the production of multiple cytokines (type 1 interferon, interleukin-6,-10, -12, and tumor necrosis factorα) by mature DC, as well as the DC-stimulated production of interferon-γ by natural killer cells. Pharmacological inhibition of glycogen synthase-3β (GSK-3β), one of the off-targets of PHA-793887, did not cause such immunological defects. Altogether, these data underscore a hitherto unsuspected immunosuppressive effect of PHA-793887.
- Published
- 2011
44. Updated technology to produce highly immunogenic dendritic cell-derived exosomes of clinical grade: a critical role of interferon-γ
- Author
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Valérie Lapierre, Thomas Tursz, Pierre-Henri Commere, Kevin Gorrichon, Clotilde Théry, Laurence Zitvogel, Stéphanie Ploix, Olivier Lantz, Dominique Tramalloni, Sophie Viaud, Pauline Virault-Rocroy, and Nathalie Chaput
- Subjects
endocrine system ,Cancer Research ,medicine.medical_treatment ,Immunology ,Antigen presentation ,Immunoblotting ,Gene Expression ,Mice, Transgenic ,CD8-Positive T-Lymphocytes ,Exosomes ,Lymphocyte Activation ,Exosome ,Cancer Vaccines ,03 medical and health sciences ,Interferon-gamma ,Mice ,0302 clinical medicine ,Antigens, Neoplasm ,polycyclic compounds ,medicine ,Immunology and Allergy ,Animals ,Humans ,Interferon gamma ,CD40 Antigens ,Antigen-presenting cell ,030304 developmental biology ,Pharmacology ,0303 health sciences ,Antigen Presentation ,business.industry ,Immunotherapy ,Dendritic cell ,Dendritic Cells ,Intercellular Adhesion Molecule-1 ,Microvesicles ,3. Good health ,030220 oncology & carcinogenesis ,B7-1 Antigen ,B7-2 Antigen ,business ,hormones, hormone substitutes, and hormone antagonists ,CD8 ,medicine.drug - Abstract
Dendritic cell-derived exosomes (Dex) are nanovesicles bearing major histocompatibility complexes promoting T-cell-dependent antitumor effects in mice. Two phase I clinical trials aimed at vaccinating cancer patients with peptide-pulsed Dex have shown the feasibility and safety of inoculating clinical-grade Dex, but have failed to show their immunizing capacity. These low immunogenic capacities have led us to develop second-generation Dex with enhanced immunostimulatory properties. Here, we show that interferon-γ is a key cytokine conditioning the dendritic cell to induce the expression of CD40, CD80, CD86, and CD54 on Dex, endowing them with direct and potent peptide-dependent CD8(+) T-cell-triggering potential in vitro and in vivo. In this study, we describe the clinical grade process to manufacture large-scale interferon-γ-Dex vaccines and their quality control parameters currently used in a phase II trial.
- Published
- 2010
45. Immunomodulatory effects of cyclophosphamide and implementations for vaccine design
- Author
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Sophie Viaud, Nathalie Chaput, Antonella Sistigu, Enrico Proietti, Laura Bracci, and Laurence Zitvogel
- Subjects
Cyclophosphamide ,business.industry ,medicine.medical_treatment ,Immunology ,Immunotherapy ,Pharmacology ,Cancer Vaccines ,Dendritic cell homeostasis ,Drug repositioning ,Cancer immunotherapy ,Drug Design ,Neoplasms ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Immunogenic cell death ,Animals ,Humans ,Cancer vaccine ,business ,Antineoplastic Agents, Alkylating ,Immunosuppressive Agents ,medicine.drug - Abstract
Drug repositioning refers to the utilization of a known compound in a novel indication underscoring a new mode of action that predicts innovative therapeutic options. Since 1959, alkylating agents, such as the lead compound cyclophosphamide (CTX), have always been conceived, at high dosages, as potent cytotoxic and lymphoablative drugs, indispensable for dose intensity and immunosuppressive regimen in the oncological and internal medicine armamentarium. However, more recent work highlighted the immunostimulatory and/or antiangiogenic effects of low dosing CTX (also called "metronomic CTX") opening up novel indications in the field of cancer immunotherapy. CTX markedly influences dendritic cell homeostasis and promotes IFN type I secretion, contributing to the induction of antitumor cytotoxic T lymphocytes and/or the proliferation of adoptively transferred T cells, to the polarization of CD4(+) T cells into TH1 and/or TH17 lymphocytes eventually affecting the Treg/Teffector ratio in favor of tumor regression. Moreover, CTX has intrinsic "pro-immunogenic" activities on tumor cells, inducing the hallmarks of immunogenic cell death on a variety of tumor types. Fifty years after its Food and Drug Administration approval, CTX remains a safe and affordable compound endowed with multifaceted properties and plethora of clinical indications. Here we review its immunomodulatory effects and advocate why low dosing CTX could be successfully combined to new-generation cancer vaccines.
- Published
- 2010
46. Modes of action of ipilimumab and biomarkers of resistance to therapy in patients
- Author
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Marie Vétizou, Dalil Hannani, Guido Kroemer, Sophie Viaud, D. Klazmann, Sylvie Rusakiewicz, Nathalie Chaput, C. Robert, Alexander M.M. Eggermont, Laurence Zitvogel, and David Enot
- Subjects
Action (philosophy) ,business.industry ,Medicine ,In patient ,Ipilimumab ,Dermatology ,Pharmacology ,business ,medicine.drug - Published
- 2013
47. Dendritic Cell-Derived Exosomes Promote Natural Killer Cell Activation and Proliferation: A Role for NKG2D Ligands and IL-15Rα
- Author
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Bernard Escudier, Fabrice Andre, Laurence Zitvogel, Thomas Tursz, Caroline Robert, Sophie Novault, Sophie Viaud, Sophie Caillat-Zucman, Julien Taieb, Nathalie Chaput, Caroline Flament, Magali Terme, Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Immunologie, génétique et traitement des maladies métaboliques et du diabète (UMR_S 561), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Vincent de Paul, Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), QLRT-2001-00093, AP-HP, ARC Institut Gustave Roussy, the Young Investigator Award, ASCO 2002, the EC Cell factory program project, ALLOSTEM European grant, the Ligue labellisée contre le cancer and Cancéropçle Ile de France., and Novault, Sophie
- Subjects
MESH: Immunotherapy ,[SDV]Life Sciences [q-bio] ,Immunology/Innate Immunity ,lcsh:Medicine ,Exosomes ,Ligands ,Lymphocyte Activation ,MESH: Cancer Vaccines ,Mice ,0302 clinical medicine ,polycyclic compounds ,MESH: Ligands ,MESH: Animals ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,MESH: Dendritic Cells ,MESH: Interleukin-15 Receptor alpha Subunit ,3. Good health ,Cell biology ,[SDV] Life Sciences [q-bio] ,Killer Cells, Natural ,medicine.anatomical_structure ,Oncology ,NK Cell Lectin-Like Receptor Subfamily K ,MESH: NK Cell Lectin-Like Receptor Subfamily K ,Immunotherapy ,Natural killer cell activation ,hormones, hormone substitutes, and hormone antagonists ,Research Article ,MESH: Killer Cells, Natural ,endocrine system ,T cell ,Immunology ,Biology ,Cancer Vaccines ,Cell Line ,03 medical and health sciences ,Interleukin-15 Receptor alpha Subunit ,MESH: Mice, Inbred C57BL ,MESH: Cell Proliferation ,medicine ,Animals ,Humans ,MESH: Exosomes ,MESH: Lymphocyte Activation ,MESH: Mice ,030304 developmental biology ,Cell Proliferation ,MESH: Humans ,Cell growth ,lcsh:R ,Dendritic cell ,Dendritic Cells ,NKG2D ,MESH: Cell Line ,Mice, Inbred C57BL ,Cell culture ,Immunology/Leukocyte Activation ,Immunology/Immune Response ,lcsh:Q ,Ex vivo ,030215 immunology - Abstract
International audience; Dendritic cell (DC) derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes promoting T cell-dependent tumor rejection. In the first Phase I trial using peptide-pulsed Dex, the observation of clinical regressions in the absence of T cell responses prompted the search for alternate effector mechanisms. Mouse studies unraveled the bioactivity of Dex on NK cells. Indeed, Dex promoted an IL-15Ralpha- and NKG2D-dependent NK cell proliferation and activation respectively, resulting in anti-metastatic effects mediated by NK1.1(+) cells. In humans, Dex express functional IL-15Ralpha which allow proliferation and IFNgamma secretion by NK cells. In contrast to immature DC, human Dex harbor NKG2D ligands on their surface leading to a direct engagement of NKG2D and NK cell activation ex vivo. In our phase I clinical trial, we highlight the capacity of Dex based-vaccines to restore the number and NKG2D-dependent function of NK cells in 7/14 patients. Altogether, these data provide a mechanistic explanation on how Dex may stimulate non MHC restricted-anti-tumor effectors and induce tumor regression in vivo.
- Published
- 2009
48. The Janus face of dendritic cells in cancer
- Author
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Alain Spatz, Rosa Conforti, Sophie Viaud, Laurence Zitvogel, and Nathalie Chaput
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Cancer Research ,Biology ,medicine.disease_cause ,Molecular oncology ,law.invention ,Antigen ,Drug Therapy ,law ,Neoplasms ,Tumor Virus ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Immunologic Surveillance ,Dendritic cell ,Dendritic Cells ,Adoptive Transfer ,Cell biology ,Immunosurveillance ,Tumor progression ,Cytoprotection ,Immunology ,Suppressor ,Tumor Escape ,Carcinogenesis - Abstract
On the basis of experimental models and some human data, we can assume that tumor outgrowth results from the balance between immunosurveillance (the extrinsic tumor suppressor mechanisms) and immunosubversion dictated by transformed cells and/or the corrupted surrounding microenvironment. Cancer immunosurveillance relies mainly upon conventional lymphocytes exerting either lytic or secretory functions, whereas immunosubversion results from the activity of regulatory T or suppressor myeloid cells and soluble mediators. Although specific tools to target or ablate dendritic cells (DCs) became only recently available, accumulating evidence points to the critical role of the specialized DC system in dictating most of the conventional and regulatory functions of tumor-specific T lymphocytes. Although DC can be harnessed to silence tumor development, tumors in turn can exploit DC to evade immunity. Indeed, DCs harbor defects in their differentiation and stimulatory functions in cancer-bearing hosts and can actively promote T-cell tolerance to self-tumor antigens. In this review, we will focus on the dual role of DC during tumor progression and discuss pharmacoimmunological strategies to harness DC against cancer.
- Published
- 2008
49. Exosomes for the treatment of human malignancies
- Author
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Sophie Viaud, Nathalie Chaput, Laurence Zitvogel, and Evelyn Ullrich
- Subjects
Cell type ,Endocrinology, Diabetes and Metabolism ,Biochemistry (medical) ,Clinical Biochemistry ,Cytoplasmic Vesicles ,General Medicine ,Dendritic Cells ,Biology ,Biochemistry ,Exosome ,Cancer Vaccines ,Microvesicles ,In vitro ,Cell biology ,Haematopoiesis ,Endocrinology ,Immune system ,Membrane protein ,Neoplasms ,Vaccines, Subunit ,Animals ,Humans ,Cancer vaccine - Abstract
Exosomes are nanometer particles (50-100 nm) secreted by most living cells. The first description of exosomes was made in 1987 by Rose Johnstone, who described a vesicle formation during the maturation process of reticulocytes. At this time it has been suggested that exosome release could represent a major route for the externalization of obsolete membrane proteins. A renewed vision of exosome function was raised when Graca Raposo demonstrated in 1996 that exosomes derived from B cells could have immunogenic capacities. Since then, exosomes have been described in numerous cell types IN VITRO, including hematopoietic and nonhematopoietic cells. The physiological relevance of exosomes IN VIVO still remains unclear. Studies have demonstrated that exosomes can play a role in the physiology of originating cells (i.e., reticulocyte-derived exosomes). Furthermore, exosomes can act on intercellular communication by allowing exchange of proteins, lipids, and also mRNA between cells. Finally, exosomes have been shown to modulate the immune system (i.e., dendritic cells, B cells, and tumor cells). In the present review, we have focused on the potential therapeutic role of exosomes as a cell free vaccine in cancer.
- Published
- 2008
50. Dendritic cell derived-exosomes: biology and clinical implementations
- Author
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Stephan Roux, Alain Spatz, Julien Taieb, Caroline Flament, Laurence Zitvogel, Jean-Bernard LePecq, Nathalie Chaput, Sophie Viaud, Fabrice Andre, Muriel Boussac, Clotilde Théry, Sebastian Amigorena, and Jérôme Garin
- Subjects
Clinical Trials, Phase I as Topic ,Endosome ,medicine.medical_treatment ,Immunology ,Antigen presentation ,Germinal center ,Cell Biology ,Immunotherapy ,Dendritic cell ,Dendritic Cells ,Endosomes ,Biology ,Cancer Vaccines ,Microvesicles ,In vitro ,Cell biology ,Neoplasms ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Humans - Abstract
Exosomes are nanometer-sized membrane vesicles invaginating from multivesicular bodies and secreted from different cell types. They represent an “in vitro” discovery, but vesicles with the hallmarks of exosomes are present in vivo in germinal centers and biological fluids. Their protein and lipid composition is unique and could account for their expanding functions such as eradication of obsolete proteins, antigen presentation, or “Trojan horses” for viruses or prions. The potential of dendritic cell-derived exosomes (Dex) as cell-free cancer vaccines is addressed in this review. Lessons learned from the pioneering clinical trials allowed reassessment of the priming capacities of Dex in preclinical models, optimizing clinical protocols, and delineating novel, biological features of Dex in cancer patients.
- Published
- 2006
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